实验性癫癎后海马新生神经元迁移分化的研究
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摘要
近年来神经科学领域最重要的研究进展之一,为发现成年哺乳动物脑内某些特定区域存在进行性的神经发生,即存在新神经元的产生。这些新生神经元整合入现有神经系统环路,发挥功能性作用。研究发现,成年海马神经发生可受多种病理生理过程的影响。
癫癎是一种常见的以反复神经元异常电发放为特征的神经系统慢性疾病。癫癎发作后,海马齿状回神经发生水平出现明显改变,这一现象为探讨癫癎后海马结构和功能可塑性的变化提供全新思路,也为癫癎的治疗带来新的曙光。但目前有关癫癎后神经前体细胞增殖、分化和新生神经元异常迁移及其调控机制等领域尚存许多空白,有必要针对性展开研究。本研究建立大、小鼠化学诱导癫癎模型,综合运用现代神经生物学研究手段,贯序性展开以下三部分研究内容:
1.不同程度癫癎发作对海马新生神经元迁移作用的研究
研究发现,癫癎发作可以增加海马齿状回神经发生的水平;且轻度及重度癫癎发作对海马NPCs增殖和分化的作用不同。但尚不知两者对齿状回新生神经元迁移的影响有何不同。
本实验建立Li-PILO诱导的轻度癫癎发作和重度癫癎发作大鼠模型,运用免疫组织化学、免疫荧光双标、及BrdU标记等技术,系统观察不同程度癫癎发作后齿状回新生神经元迁移的情况;并对导致异常迁移可能的分子机制进行了初步探索。结果如下:
⑴正常及轻度癫癎发作大鼠海马内,新生细胞迁移入颗粒细胞层,但严重癫癎发作后新生细胞迁移方向出现异常,多数迁移入齿状回门区。
⑵严重癫癎发作后,新生神经元表现出异常迁移模式,形成异位门区基树突和门区异位神经元。
⑶严重癫癎发作导致星形胶质细胞激活并表达nestin,而轻度癫癎发作后,海马中几无nestin阳性细胞。
⑷严重癫癎发作导致齿状回门区内表达迁移诱向分子netrin 1和Sema-3A,而正常及轻度癫癎发作大鼠门区内未观察到这些分子的表达。
以上结果提示,SE后齿状回门区内发育期神经诱向分子表达,这可能是门区异位神经元形成的原因。
2.星形胶质细胞和小胶质细胞对癫癎后海马异常神经发生的研究
建立Li-PILO诱导的SE模型,结合立体定位注射、免疫组化以及FJB染色等技术,观察癫癎后星形胶质细胞和小胶质细胞的时空激活特点;进而分别干预二者的激活水平,观察其对新生神经元异常迁移的影响。实验结果如下:
⑴SE后3-20天,海马齿状回内星形胶质细胞和小胶质细胞均出现长程激活,并随时间推移表现出数量变化和形态差别。
⑵通过向齿状回门区注射氟代柠檬酸(FC),抑制星形胶质细胞代谢,发现FC注射后不能阻断癫癎后异位门区基树突的形成,但加剧了癫癎后齿状回颗粒细胞的变性损伤。
⑶通过给予米诺环素(MC)选择性抑制小胶质细胞激活,发现在SE 14天时,新生神经元向门区的异常迁移被有效抑制。
⑷向正常齿状回门区内注射小胶质细胞激活剂LPS。注射后3天,齿状回内出现异位门区基树突的形成。
上述结果提示,癫癎发作后齿状回门区内激活的小胶质细胞可能引导了新生神经元向门区的异常迁移,MC可能是一种潜在药物,阻止癫癎发作导致的新生神经元异常迁移。
3.癫癎发生过程中海马内GABA能神经发生的研究
癫癎发作可导致海马新生神经元异常迁移,参与癫癎发生过程,最终形成慢性癫癎。但癫癎发生过程中是否存在神经前体细胞(NPCs)向抑制性γ-氨基丁酸(GABA)能神经元分化,尚不明确。本研究利用特异性显示抑制性GABA能神经元的谷氨酸脱羧酶(GAD)67-绿色荧光蛋白(GFP)基因敲入小鼠,建立戊四氮(PTZ)慢性点燃模型和锂(Li)-匹罗卡品(PILO)诱导的癫癎状态(SE)模型,结合免疫组化、免疫荧光标记、BrdU标记等技术,观察两种癫癎模型中海马齿状回神经发生的情况,以及抑制性GABA能神经元的新生和存活。结果如下:
⑴癫癎发作后早期阶段,两种癫癎模型均诱导海马齿状回新生细胞数量显著增加;PTZ点燃后2周和SE后8周,新生细胞数量均明显减少。
⑵正常对照组中,约80%的新生细胞分化为神经元;而PTZ点燃组和SE组中,分别仅有58%和29%的新生细胞分化为神经元。
⑶免疫荧光双标记、三标记结果显示,在正常对照组和癫癎组中,齿状回新生细胞均不能分化为GAD67阳性的GABA能神经元。
⑷在SE模型,而非PTZ点燃模型中,海马齿状回内GABA能神经元总数显著减少。
上述结果提示,不同类型癫癎发作对海马神经发生的影响不尽相同;而无论何种发作,齿状回内均未发现存在新GAD67阳性GABA能神经元的产生;但长期癫癎发作可导致齿状回GABA能神经元的丢失。
It is among the most exciting and fasting progressing areas of neuroscience today, the study of adult neurogenesis, i.e. new neurons are continually being generated in adult mammalian brain. These newborn neurons eventually integrate into existing neuronal circuitries to exert functional effects. Mounting evidence suggests that ongoing neurogenesis in discrete brain regions not only occurs in normal adult mammalian animals, but also is modulated by multiple physiological factors and pathological events.
Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures, which are transient signs and/or symptoms of abnormal, excessive or synchronous neuronal activity in the brain. Epileptic seizures can lead to a drastic change of neurogenesis in hippocampal dentate gyrus. The phenomenon provides a brand new clue for investigating the plasticity of hippocampal structure and function after epileptic seizures, and also brings a new therapeutic strategy for treatment of epilepsy. However, the proliferation and differentiation of neural progenitor cells and the aberrant migration of newborn neurons after epileptic seizures, and its regulating mechanism in hippocampus remain largely unknown.
In the study, we employed experimental epilepsy models in adult rodents, and performed the sequential three parts of the experiment by using multiple contemporary neurobiological techniques.
1. Different Effects of Mild and Severe Seizures on the Migration of Hippocampal Newborn Neurons in Adult Rats
Recent evidence shows that epileptic seizures can increase neurogenesis in the dentate gyrus and that mild and severe seizures induce different effects on hippocampal neural progenitors proliferation and differentiation. However, it is unknown whether different seizure severity has different effects on newborn neurons migration in the DG of adult rats.
We established Li-PILO-induced mild and severe epileptic seizures models. Then we sought to examine the effects of different seizure severity on the migration of newborn cells in the dentate gyrus using immunohistochemistry, double immunefluorescence labeling and BrdU-labeling dividing cells methods. In addition, we further investigated the potential molecular mechanism underlying these processes. The results were as followings:
⑴Most newborn neurons migrated into the granular cell layer in control and mild seizure groups, but severe seizures were associated with an aberrant migration of newborn neurons into the dentate hilus.
⑵Severe epileptic seizures induced the formation of aberrant hilar basal dendrites and hilar-ectopic newborn neurons.
⑶Severe seizures induced astrocyte activation and the expression of nestin, which was hardly seen in mild epileptic hippocampus.
⑷Severe seizures induced the expression of the migration directional molecules netrin 1 and Sema-3A in the hilus, which were not present in the hilus of control and mild seizure-attacked rats,
These results suggesting that severe seizures induce the expression of migration guiding molecules related to brain development, which may play a role in the aberrant migration of newborn neurons.
2. Roles of Astrocytes and Microglia in Seizure-induced Aberrant Neurogenesis in the Hippocampus of Adult Rats
In this study, we established Li-PILO-induced SE model. By using hilar stereotaxic injection, immunohistochemistry and FJB staining methods, we examined activated patterns of astrocytes and microglia in epileptic dentate gyrus, then, observed the effects of activated astrocytes and microglia on aberrant migration of newborn neurons, respectively. The results were as followings:
⑴SE induced a prominent activation of astrocytes and microglia in the dentate gyrus 3, 7, 14, and 20 days after the initial seizures.
⑵By injecting fluorocitrate (FC) stereotaxicly into the hilus to inhibit astrocytic metabolism, we found that FC failed to prevent seizure-induced the formation of aberrant hilar basal dendrites, but instead promoted the degeneration of dentate granule cells after seizures.
⑶In contrast, a selective inhibitor of microglia activation, minocycline (MC), inhibited the aberrant migration of newborn neurons at 14 days after status epilepticus.
⑷By stereotaxic injection of lipopolysaccharide (LPS) into the intact dentate hilus to activate local microglia, we found that LPS promoted the development of aberrant hilar basal dendrites in the dentate gyrus.
These results indicate that the activated microglia in the epileptic hilus may guide the aberrant migration of newborn neurons, and that MC could be a potential drug to impede seizure-induced aberrant migration of newborn neurons.
3. No GAD67-Positive GABAergic Neurogenesis in the Dentate Gyrus of Adult Mice in Experimental Epilepsy Models
Mounting evidence shows that epileptic seizures influence normal migration pattern of hippocampal newborn neurons, which plays a role in the process of epileptogenesis and eventually contributes to the formation of chronic epilepsy. However, it is unknown whether the newborn neurons in the epileptic hippocampus can differentiate into inhibitory neurons, i.e.γ-aminobutyric acid (GABA) ergic interneurons. Here, we investigated the GABAergic neurogenesis in the epileptic hippocampus. By using glutamic acid decarboxylase (GAD) 67 -green fluorescence protein (GFP) knock-in mice, in which a GFP gene was introduced into the gene for GAD67 and thus all GABAergic neurons were fluorescent, we could easily observe green-fluorescent cells as GABAergic neurons containing GAD67. We employed pentylenetetrazol (PTZ)-induced chronic kindling model to mimic human generalized epilepsy, and lithium (Li) -pilocarpine (PILO) -induced status epilepticus (SE) model to reproduce human partial epilepsy. The results were as followings:
⑴Both types of epilepsy significantly increased the number of newborn cells in the dentate gyrus at early time-point after seizures; however, there is a significant loss of newborn cells at 2 weeks after PTZ kindling and 8 weeks after Li-PILO-induced seizures.
⑵About 80% of newborn dentate cells differentiated into neurons in control groups, whereas only 58% and 29% of newborn cells differentiated into neurons in the PTZ-kindling and Li-PILO models, respectively.
⑶Double or triple immunofluorescence labeling did not reveal any newborn cells co-labeled with GFP in both intact and epileptic dentate gyrus.
⑷A significant decrease in the total number of GABAergic neurons in the dentate gyrus was detected in the SE model but not in the PTZ-kindling model.
These results indicate that epileptic seizures do not produce new GAD67-positive GABAergic interneurons in the dentate gyrus, but instead prolonged seizures result in the loss of GABAergic interneurons.
癫癎是一种常见的以反复神经元异常电发放为特征的神经系统慢性疾病。癫癎发作后,海马齿状回神经发生水平出现明显改变,这一现象为探讨癫癎后海马结构和功能可塑性的变化提供全新思路,也为癫癎的治疗带来新的曙光。但目前有关癫癎后神经前体细胞增殖、分化和新生神经元异常迁移及其调控机制等领域尚存许多空白,有必要针对性展开研究。本研究建立大、小鼠化学诱导癫癎模型,综合运用现代神经生物学研究手段,贯序性展开以下三部分研究内容:
1.不同程度癫癎发作对海马新生神经元迁移作用的研究
研究发现,癫癎发作可以增加海马齿状回神经发生的水平;且轻度及重度癫癎发作对海马NPCs增殖和分化的作用不同。但尚不知两者对齿状回新生神经元迁移的影响有何不同。
本实验建立Li-PILO诱导的轻度癫癎发作和重度癫癎发作大鼠模型,运用免疫组织化学、免疫荧光双标、及BrdU标记等技术,系统观察不同程度癫癎发作后齿状回新生神经元迁移的情况;并对导致异常迁移可能的分子机制进行了初步探索。结果如下:
⑴正常及轻度癫癎发作大鼠海马内,新生细胞迁移入颗粒细胞层,但严重癫癎发作后新生细胞迁移方向出现异常,多数迁移入齿状回门区。
⑵严重癫癎发作后,新生神经元表现出异常迁移模式,形成异位门区基树突和门区异位神经元。
⑶严重癫癎发作导致星形胶质细胞激活并表达nestin,而轻度癫癎发作后,海马中几无nestin阳性细胞。
⑷严重癫癎发作导致齿状回门区内表达迁移诱向分子netrin 1和Sema-3A,而正常及轻度癫癎发作大鼠门区内未观察到这些分子的表达。
以上结果提示,SE后齿状回门区内发育期神经诱向分子表达,这可能是门区异位神经元形成的原因。
2.星形胶质细胞和小胶质细胞对癫癎后海马异常神经发生的研究
建立Li-PILO诱导的SE模型,结合立体定位注射、免疫组化以及FJB染色等技术,观察癫癎后星形胶质细胞和小胶质细胞的时空激活特点;进而分别干预二者的激活水平,观察其对新生神经元异常迁移的影响。实验结果如下:
⑴SE后3-20天,海马齿状回内星形胶质细胞和小胶质细胞均出现长程激活,并随时间推移表现出数量变化和形态差别。
⑵通过向齿状回门区注射氟代柠檬酸(FC),抑制星形胶质细胞代谢,发现FC注射后不能阻断癫癎后异位门区基树突的形成,但加剧了癫癎后齿状回颗粒细胞的变性损伤。
⑶通过给予米诺环素(MC)选择性抑制小胶质细胞激活,发现在SE 14天时,新生神经元向门区的异常迁移被有效抑制。
⑷向正常齿状回门区内注射小胶质细胞激活剂LPS。注射后3天,齿状回内出现异位门区基树突的形成。
上述结果提示,癫癎发作后齿状回门区内激活的小胶质细胞可能引导了新生神经元向门区的异常迁移,MC可能是一种潜在药物,阻止癫癎发作导致的新生神经元异常迁移。
3.癫癎发生过程中海马内GABA能神经发生的研究
癫癎发作可导致海马新生神经元异常迁移,参与癫癎发生过程,最终形成慢性癫癎。但癫癎发生过程中是否存在神经前体细胞(NPCs)向抑制性γ-氨基丁酸(GABA)能神经元分化,尚不明确。本研究利用特异性显示抑制性GABA能神经元的谷氨酸脱羧酶(GAD)67-绿色荧光蛋白(GFP)基因敲入小鼠,建立戊四氮(PTZ)慢性点燃模型和锂(Li)-匹罗卡品(PILO)诱导的癫癎状态(SE)模型,结合免疫组化、免疫荧光标记、BrdU标记等技术,观察两种癫癎模型中海马齿状回神经发生的情况,以及抑制性GABA能神经元的新生和存活。结果如下:
⑴癫癎发作后早期阶段,两种癫癎模型均诱导海马齿状回新生细胞数量显著增加;PTZ点燃后2周和SE后8周,新生细胞数量均明显减少。
⑵正常对照组中,约80%的新生细胞分化为神经元;而PTZ点燃组和SE组中,分别仅有58%和29%的新生细胞分化为神经元。
⑶免疫荧光双标记、三标记结果显示,在正常对照组和癫癎组中,齿状回新生细胞均不能分化为GAD67阳性的GABA能神经元。
⑷在SE模型,而非PTZ点燃模型中,海马齿状回内GABA能神经元总数显著减少。
上述结果提示,不同类型癫癎发作对海马神经发生的影响不尽相同;而无论何种发作,齿状回内均未发现存在新GAD67阳性GABA能神经元的产生;但长期癫癎发作可导致齿状回GABA能神经元的丢失。
It is among the most exciting and fasting progressing areas of neuroscience today, the study of adult neurogenesis, i.e. new neurons are continually being generated in adult mammalian brain. These newborn neurons eventually integrate into existing neuronal circuitries to exert functional effects. Mounting evidence suggests that ongoing neurogenesis in discrete brain regions not only occurs in normal adult mammalian animals, but also is modulated by multiple physiological factors and pathological events.
Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures, which are transient signs and/or symptoms of abnormal, excessive or synchronous neuronal activity in the brain. Epileptic seizures can lead to a drastic change of neurogenesis in hippocampal dentate gyrus. The phenomenon provides a brand new clue for investigating the plasticity of hippocampal structure and function after epileptic seizures, and also brings a new therapeutic strategy for treatment of epilepsy. However, the proliferation and differentiation of neural progenitor cells and the aberrant migration of newborn neurons after epileptic seizures, and its regulating mechanism in hippocampus remain largely unknown.
In the study, we employed experimental epilepsy models in adult rodents, and performed the sequential three parts of the experiment by using multiple contemporary neurobiological techniques.
1. Different Effects of Mild and Severe Seizures on the Migration of Hippocampal Newborn Neurons in Adult Rats
Recent evidence shows that epileptic seizures can increase neurogenesis in the dentate gyrus and that mild and severe seizures induce different effects on hippocampal neural progenitors proliferation and differentiation. However, it is unknown whether different seizure severity has different effects on newborn neurons migration in the DG of adult rats.
We established Li-PILO-induced mild and severe epileptic seizures models. Then we sought to examine the effects of different seizure severity on the migration of newborn cells in the dentate gyrus using immunohistochemistry, double immunefluorescence labeling and BrdU-labeling dividing cells methods. In addition, we further investigated the potential molecular mechanism underlying these processes. The results were as followings:
⑴Most newborn neurons migrated into the granular cell layer in control and mild seizure groups, but severe seizures were associated with an aberrant migration of newborn neurons into the dentate hilus.
⑵Severe epileptic seizures induced the formation of aberrant hilar basal dendrites and hilar-ectopic newborn neurons.
⑶Severe seizures induced astrocyte activation and the expression of nestin, which was hardly seen in mild epileptic hippocampus.
⑷Severe seizures induced the expression of the migration directional molecules netrin 1 and Sema-3A in the hilus, which were not present in the hilus of control and mild seizure-attacked rats,
These results suggesting that severe seizures induce the expression of migration guiding molecules related to brain development, which may play a role in the aberrant migration of newborn neurons.
2. Roles of Astrocytes and Microglia in Seizure-induced Aberrant Neurogenesis in the Hippocampus of Adult Rats
In this study, we established Li-PILO-induced SE model. By using hilar stereotaxic injection, immunohistochemistry and FJB staining methods, we examined activated patterns of astrocytes and microglia in epileptic dentate gyrus, then, observed the effects of activated astrocytes and microglia on aberrant migration of newborn neurons, respectively. The results were as followings:
⑴SE induced a prominent activation of astrocytes and microglia in the dentate gyrus 3, 7, 14, and 20 days after the initial seizures.
⑵By injecting fluorocitrate (FC) stereotaxicly into the hilus to inhibit astrocytic metabolism, we found that FC failed to prevent seizure-induced the formation of aberrant hilar basal dendrites, but instead promoted the degeneration of dentate granule cells after seizures.
⑶In contrast, a selective inhibitor of microglia activation, minocycline (MC), inhibited the aberrant migration of newborn neurons at 14 days after status epilepticus.
⑷By stereotaxic injection of lipopolysaccharide (LPS) into the intact dentate hilus to activate local microglia, we found that LPS promoted the development of aberrant hilar basal dendrites in the dentate gyrus.
These results indicate that the activated microglia in the epileptic hilus may guide the aberrant migration of newborn neurons, and that MC could be a potential drug to impede seizure-induced aberrant migration of newborn neurons.
3. No GAD67-Positive GABAergic Neurogenesis in the Dentate Gyrus of Adult Mice in Experimental Epilepsy Models
Mounting evidence shows that epileptic seizures influence normal migration pattern of hippocampal newborn neurons, which plays a role in the process of epileptogenesis and eventually contributes to the formation of chronic epilepsy. However, it is unknown whether the newborn neurons in the epileptic hippocampus can differentiate into inhibitory neurons, i.e.γ-aminobutyric acid (GABA) ergic interneurons. Here, we investigated the GABAergic neurogenesis in the epileptic hippocampus. By using glutamic acid decarboxylase (GAD) 67 -green fluorescence protein (GFP) knock-in mice, in which a GFP gene was introduced into the gene for GAD67 and thus all GABAergic neurons were fluorescent, we could easily observe green-fluorescent cells as GABAergic neurons containing GAD67. We employed pentylenetetrazol (PTZ)-induced chronic kindling model to mimic human generalized epilepsy, and lithium (Li) -pilocarpine (PILO) -induced status epilepticus (SE) model to reproduce human partial epilepsy. The results were as followings:
⑴Both types of epilepsy significantly increased the number of newborn cells in the dentate gyrus at early time-point after seizures; however, there is a significant loss of newborn cells at 2 weeks after PTZ kindling and 8 weeks after Li-PILO-induced seizures.
⑵About 80% of newborn dentate cells differentiated into neurons in control groups, whereas only 58% and 29% of newborn cells differentiated into neurons in the PTZ-kindling and Li-PILO models, respectively.
⑶Double or triple immunofluorescence labeling did not reveal any newborn cells co-labeled with GFP in both intact and epileptic dentate gyrus.
⑷A significant decrease in the total number of GABAergic neurons in the dentate gyrus was detected in the SE model but not in the PTZ-kindling model.
These results indicate that epileptic seizures do not produce new GAD67-positive GABAergic interneurons in the dentate gyrus, but instead prolonged seizures result in the loss of GABAergic interneurons.
引文
1. Koelliker A. Handbuch der Gerebelehre des Menschen: Engelmann, Leipzig, 1896
2. Ramon y Cajal S. Texture of the Nervous System of Man and Vertebrates (Trans. Pasik, P. & Pasik, T., from the 1899-1904 Spanish adn): Springer, Vienna, 1999
3. Ramon y Cajal S. Degeneration and Regeneration of the Neuvous System (Trans. Day, R.M., From the 1913 Spanish edn): Oxford Univ. Press, London, 1928
4. Jacobson M. Development Neurobiology: Holt, Rinehart, and Winston, New York, 1970
5. Altman J. Autoradiographic investigation of cell proliferation in the brains of rats and cats. Anat Rec. 1963;145:573-591
6. Altman J. Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol. 1969;137:433-457
7. Kaplan MS, Hinds JW. Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science. 1977;197:1092-1094
8. Rakic P. Limits of neurogenesis in primates. Science. 1985;227:1054-1056
9. Alvarez-Buylla A, Nottebohm F. Migration of young neurons in adult avian brain. Nature. 1988;335:353-354
10. Alvarez-Buylla A, Theelen M, Nottebohm F. Birth of projection neurons in the higher vocal center of the canary forebrain before, during, and after song learning. Proc Natl Acad Sci U S A. 1988;85:8722-8726
11. Burd GD, Nottebohm F. Ultrastructural characterization of synaptic terminals formed on newly generated neurons in a song control nucleus of the adult canary forebrain. J Comp Neurol. 1985;240:143-152
12. Paton JA, Nottebohm FN. Neurons generated in the adult brain are recruited into functional circuits. Science. 1984;225:1046-1048
13. Gould E, Cameron HA, Daniels DC et al. Adrenal hormones suppress cell division in the adult rat dentate gyrus. J Neurosci. 1992;12:3642-3650
14. Cameron HA, Woolley CS, McEwen BS, Gould E. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience. 1993;56:337-344
15. Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996;16:2027-2033
16. Gould E, McEwen BS, Tanapat P et al. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci. 1997;17:2492-2498
17. Gould E, Reeves AJ, Fallah M et al. Hippocampal neurogenesis in adult Old World primates. Proc Natl Acad Sci U S A. 1999;96:5263-5267
18. Kornack DR, Rakic P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci U S A. 1999;96:5768-5773
19. Eriksson PS, Perfilieva E, Bjork-Eriksson T et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4:1313-1317
20. van Praag H, Schinder AF, Christie BR et al. Functional neurogenesis in the adult hippocampus. Nature. 2002;415:1030-1034
21. Ramirez-Amaya V, Marrone DF, Gage FH et al. Integration of new neurons into functional neural networks. J Neurosci. 2006;26:12237-12241
22. Lois C, Alvarez-Buylla A. Long-distance neuronal migration in the adult mammalian brain. Science. 1994;264:1145-1148
23. Corotto FS, Henegar JR, Maruniak JA. Odor deprivation leads to reduced neurogenesis and reduced neuronal survival in the olfactory bulb of the adult mouse. Neuroscience. 1994;61:739-744
24. Bedard A, Parent A. Evidence of newly generated neurons in thehuman olfactory bulb. Brain Res Dev Brain Res. 2004;151:159-168
25. Sanai N, Tramontin AD, Quinones-Hinojosa A et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature. 2004;427:740-744
26. Curtis MA, Kam M, Nannmark U et al. Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science. 2007;315:1243-1249
27. Kaplan MS. Neurogenesis in the 3-month-old rat visual cortex. J Comp Neurol. 1981;195:323-338
28. Huang L, DeVries GJ, Bittman EL. Photoperiod regulates neuronal bromodeoxyuridine labeling in the brain of a seasonally breeding mammal. J Neurobiol. 1998;36:410-420
29. Dayer AG, Cleaver KM, Abouantoun T, Cameron HA. New GABAergic interneurons in the adult neocortex and striatum are generated from different precursors. J Cell Biol. 2005;168:415-427
30. Gould E, Reeves AJ, Graziano MS, Gross CG. Neurogenesis in the neocortex of adult primates. Science. 1999;286:548-552
31. Kodama M, Fujioka T, Duman RS. Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol Psychiatry. 2004;56:570-580
32. Ehninger D, Kempermann G. Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex. Cereb Cortex. 2003;13:845-851
33. Kornack DR, Rakic P. Cell proliferation without neurogenesis in adult primate neocortex. Science. 2001;294:2127-2130
34. Bhardwaj RD, Curtis MA, Spalding KL et al. Neocortical neurogenesis in humans is restricted to development. Proc Natl Acad Sci U S A. 2006;103:12564-12568
35. Luzzati F, De Marchis S, Fasolo A, Peretto P. Neurogenesis in the caudate nucleus of the adult rabbit. J Neurosci. 2006;26:609-621
36. Fowler CD, Johnson F, Wang Z. Estrogen regulation of cell proliferation and distribution of estrogen receptor-alpha in the brains of adult female prairie and meadow voles. J Comp Neurol.2005;489:166-179
37. Kokoeva MV, Yin H, Flier JS. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science. 2005;310:679-683
38. Zhao M, Momma S, Delfani K et al. Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci U S A. 2003;100:7925-7930
39. Bauer S, Hay M, Amilhon B et al. In vivo neurogenesis in the dorsal vagal complex of the adult rat brainstem. Neuroscience. 2005;130:75-90
40. Bedard A, Levesque M, Bernier PJ, Parent A. The rostral migratory stream in adult squirrel monkeys: contribution of new neurons to the olfactory tubercle and involvement of the antiapoptotic protein Bcl-2. Eur J Neurosci. 2002;16:1917-1924
41. Pekcec A, Loscher W, Potschka H. Neurogenesis in the adult rat piriform cortex. Neuroreport. 2006;17:571-574
42. Chmielnicki E, Benraiss A, Economides AN, Goldman SA. Adenovirally expressed noggin and brain-derived neurotrophic factor cooperate to induce new medium spiny neurons from resident progenitor cells in the adult striatal ventricular zone. J Neurosci. 2004;24:2133-2142
43. Park JH, Cho H, Kim H, Kim K. Repeated brief epileptic seizures by pentylenetetrazole cause neurodegeneration and promote neurogenesis in discrete brain regions of freely moving adult rats. Neuroscience. 2006;140:673-684
44. Frielingsdorf H, Schwarz K, Brundin P, Mohapel P. No evidence for new dopaminergic neurons in the adult mammalian substantia nigra. Proc Natl Acad Sci U S A. 2004;101:10177-10182
45. Gould E. How widespread is adult neurogenesis in mammals? Nat Rev Neurosci. 2007;8:481-488
46. Bonfanti L. PSA-NCAM in mammalian structural plasticity and neurogenesis. Prog Neurobiol. 2006;80:129-164
47. Poulsen FR, Blaabjerg M, Montero M, Zimmer J. Glutamate receptorantagonists and growth factors modulate dentate granule cell neurogenesis in organotypic, rat hippocampal slice cultures. Brain Res. 2005;1051:35-49
48. von Bohlen Und Halbach O. Immunohistological markers for staging neurogenesis in adult hippocampus. Cell Tissue Res. 2007;329:409-420
49. Jessberger S, Gage FH, Eisch AJ, Lagace DC. Making a neuron: Cdk5 in embryonic and adult neurogenesis. Trends Neurosci. 2009;32:575-582
50. Zhao C, Teng EM, Summers RG, Jr. et al. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci. 2006;26:3-11
51. Carpenter MB, Sutin J. Human Neuroanatomy, 8th ed: Baltimore/London: Williams & Wilkins, 1983
52. Eisch AJ, Cameron HA, Encinas JM et al. Adult neurogenesis, mental health, and mental illness: hope or hype? J Neurosci. 2008;28:11785-11791
53. Schinder AF, Gage FH. A hypothesis about the role of adult neurogenesis in hippocampal function. Physiology (Bethesda). 2004;19:253-261
54. Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol. 2000;425:479-494
55. Duan X, Kang E, Liu CY et al. Development of neural stem cell in the adult brain. Curr Opin Neurobiol. 2008;18:108-115
56. Kempermann G, Wiskott L, Gage FH. Functional significance of adult neurogenesis. Curr Opin Neurobiol. 2004;14:186-191
57. Kempermann G, Gast D, Kronenberg G et al. Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development. 2003;130:391-399
58. Stanfield BB, Trice JE. Evidence that granule cells generated in the dentate gyrus of adult rats extend axonal projections. Exp Brain Res. 1988;72:399-406
59. Markakis EA, Gage FH. Adult-generated neurons in the dentate gyrussend axonal projections to field CA3 and are surrounded by synaptic vesicles. J Comp Neurol. 1999;406:449-460
60. Alvarez-Buylla A, Lim DA. For the long run: maintaining germinal niches in the adult brain. Neuron. 2004;41:683-686
61. Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci. 2005;28:223-250
62. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008;132:645-660
63. Lie DC, Colamarino SA, Song HJ et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005;437:1370-1375
64. Bonaguidi MA, McGuire T, Hu M et al. LIF and BMP signaling generate separate and discrete types of GFAP-expressing cells. Development. 2005;132:5503-5514
65. Ueki T, Tanaka M, Yamashita K et al. A novel secretory factor, Neurogenesin-1, provides neurogenic environmental cues for neural stem cells in the adult hippocampus. J Neurosci. 2003;23:11732-11740
66. Gong C, Wang TW, Huang HS, Parent JM. Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus. J Neurosci. 2007;27:1803-1811
67. Jessberger S, Aigner S, Clemenson GD, Jr. et al. Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus. PLoS Biol. 2008;6:e272
68. Duan X, Chang JH, Ge S et al. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007;130:1146-1158
69. Ge S, Goh EL, Sailor KA et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature. 2006;439:589-593
70. Breunig JJ, Silbereis J, Vaccarino FM et al. Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus. Proc Natl Acad Sci U S A. 2007;104:20558-20563
71. Ge S, Pradhan DA, Ming GL, Song H. GABA sets the tempo for activity-dependent adult neurogenesis. Trends Neurosci. 2007;30:1-8
72. Esposito MS, Piatti VC, Laplagne DA et al. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J Neurosci. 2005;25:10074-10086
73. Gould E, Tanapat P, Hastings NB, Shors TJ. Neurogenesis in adulthood: a possible role in learning. Trends Cogn Sci. 1999;3:186-192
74. Leuner B, Gould E, Shors TJ. Is there a link between adult neurogenesis and learning? Hippocampus. 2006;16:216-224
75. Sisti HM, Glass AL, Shors TJ. Neurogenesis and the spacing effect: learning over time enhances memory and the survival of new neurons. Learn. Mem. 2007;14:368-375
76. Drapeau E, Montaron MF, Aguerre S, Abrous DN. Learning induced survival of new neurons depends on the cognitive status of aged rats. J. Neurosci. . 2007;27:6037-6044
77. Dupret D, Fabre A, Dobrossy MD et al. Spatial learning depends on both the addition and removal of new hippocampal neurons. PLoS Biol. . 2007;5:e214
78. Dobrossy MD, Drapeau E, Aurousseau C et al. Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date. Mol. Psychiatry. 2003;8:974-982
79. Olariu A, Yamada K, Nabeshima T. Amyloid pathology and protein kinase C (PKC): possible therapeutics effects of PKC activators. J. Pharmacol. Sci. 2005;97:1-5
80. Snyder JS, Hong NS, McDonald RJ, Wojtowicz JM. A role for adult neurogenesis in spatial long-term memory. Neuroscience. 2005;130:843-852
81. Shors TJ, Miesegaes G, Beylin A et al. Neurogenesis in the adult is involved in the formation of trace memories. Nature. 2001;410:372-376
82. Saxe MD, Battaglia F, Wang JW et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc. Natl. Acad. Sci. USA. 2006;103:17501-17506
83. Winocur G, Wojtowicz JM, Sekeres M et al. Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus. 2006;16:296-304
84. Zhang C-L, Zou Y, He W et al. A role for adult TLX-positive neural stem cells in learning and behaviour. Nature. 2008;451:1004-1007
85. Mirescu C, Gould E. Stress and adult neurogenesis. Hippocampus. 2006;16:233-238
86. Shors TJ, Mathew J, Sisti HM et al. Neurogenesis and helplessness are mediated by controllability in males but not in females. Biol. Psychiatry. 2007;62: 487-495
87. Warner-Schmidt JL, Duman RS. Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus. 2006;16:239-249
88. Encinas JM, Vaahtokari A, Enikolopov G. Fluoxetine targets early progenitor cells in the adult brain. Proc Natl Acad Sci U S A. 2006;103:8233-8238
89. Santarelli L, Saxe M, Gross C et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805-809
90. Jiang W, Zhang Y, Xiao L et al. Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J Clin Invest. 2005;115:3104-3116
91. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry. 2006;59:1116-1127
92. Rossi C, Angelucci A, Costantin L et al. Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. Eur. J. Neurosci. . 2006;24:1850-1856
93. Warner-Schmidt JL, Duman RS. VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc. Natl. Acad. Sci. USA. 2007;104:4647-4652
94. Malberg JE, Platt B, Rizzo SJ et al. Increasing the levels of insulin-like growth factor-I by an IGF binding protein inhibitor producesanxiolytic and antidepressant-like effects. Neuropsychopharmacology. 2007;32:2360-2368
95. Earnheart JC, Schweizer C, Crestani F et al. GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J. Neurosci. 2007;27:3845-3854
96. Kempermann G, Gage FH. Genetic determinants of adult hippocampal neurogenesis correlate with acquisition, but not probe trial performance, in the water maze task. Eur J Neurosci. 2002;16:129-136
97. Olson AK, Eadie BD, Ernst C, Christie BR. Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus. 2006;16:250-260
98. van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999;2:266-270
99. Kee N, Teixeira CM, Wang AH, Frankland PW. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. . Nat. Neurosci. . 2007;10:355-362
100. Tashiro A, Makino H, Gage FH. Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J. Neurosci. . 2007;.27:3252-3259
101. Bruel-Jungerman E, Laroche S, Rampon C. New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur. J. Neurosci. 2005;21:513-521
102. Klempin F, Kempermann G. Adult hippocampal neurogenesis and aging. Eur. Arch. Psychiatry Clin. Neurosci. . 2007;257: 271-280
103. van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. . 2005;25:8680-8685
104. Imai F, Suzuki H, Oda J et al. Neuroprotective effect of exogenous microglia in global brain ischemia. J Cereb Blood Flow Metab. 2007;27:488-500
105. Jin K, Wang X, Xie L et al. Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci U S A. 2006;103:13198-13202
106. Tonchev AB, Yamashima T, Zhao L et al. Proliferation of neural and neuronal progenitors after global brain ischemia in young adult macaque monkeys. Mol Cell Neurosci. 2003;23:292-301
107. Liu J, Bartels M, Lu A, Sharp FR. Microglia/macrophages proliferate in striatum and neocortex but not in hippocampus after brief global ischemia that produces ischemic tolerance in gerbil brain. J Cereb Blood Flow Metab. 2001;21:361-373
108. Liu J, Solway K, Messing RO, Sharp FR. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci. 1998;18:7768-7778
109. Dempsey RJ, Sailor KA, Bowen KK et al. Stroke-induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: effect of exogenous IGF-1 and GDNF. J Neurochem. 2003;87:586-597
110. Zhu DY, Liu SH, Sun HS, Lu YM. Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus. J Neurosci. 2003;23:223-229
111. Naylor M, Bowen KK, Sailor KA et al. Preconditioning-induced ischemic tolerance stimulates growth factor expression and neurogenesis in adult rat hippocampus. Neurochem Int. 2005;47:565-572
112. Komitova M, Perfilieva E, Mattsson B et al. Effects of cortical ischemia and postischemic environmental enrichment on hippocampal cell genesis and differentiation in the adult rat. J Cereb Blood Flow Metab. 2002;22:852-860
113. Ninomiya M, Yamashita T, Araki N et al. Enhanced neurogenesis in the ischemic striatum following EGF-induced expansion of transit-amplifying cells in the subventricular zone. Neurosci Lett. 2006;403:63-67
114. Jin K, Mao XO, Sun Y et al. Heparin-binding epidermal growth factor-like growth factor: hypoxia-inducible expression in vitro and stimulation of neurogenesis in vitro and in vivo. J Neurosci. 2002;22:5365-5373
115. Yan YP, Sailor KA, Vemuganti R, Dempsey RJ. Insulin-like growth factor-1 is an endogenous mediator of focal ischemia-induced neural progenitor proliferation. Eur J Neurosci. 2006;24:45-54
116. Nakatomi H, Kuriu T, Okabe S et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell. 2002;110:429-441
117. Tureyen K, Vemuganti R, Bowen KK et al. EGF and FGF-2 infusion increases post-ischemic neural progenitor cell proliferation in the adult rat brain. Neurosurgery. 2005;57:1254-1263; discussion 1254-1263
118. Wang L, Zhang Z, Wang Y et al. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke. 2004;35:1732-1737
119. Nygren J, Kokaia M, Wieloch T. Decreased expression of brainderived neurotrophic factor in BDNF+/-. Mice is associated with enhanced recovery of motor performance and increased neuroblast number following experimental stroke. J. Neurosci. Res. 2006;84: 626–631
120. Boekhoorn K, Joels M, Lucassen PJ. Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis. 2006;24:1-14
121. Jin K, Peel AL, Mao XO et al. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004;101:343-347
122. Donovan MH, Yazdani U, Norris RD et al. Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease. J Comp Neurol. 2006;495:70-83
123. Zhang C, McNeil E, Dressler L, Siman R. Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer's disease. Exp Neurol. 2007;204:77-87
124. Pillon B, Ertle S, Deweer B et al. Memory for spatial location in 'de novo' parkinsonian patients. Neuropsychologia. 1997;35:221-228
125. Oertel WH, Hoglinger GU, Caraceni T et al. Depression in Parkinson's disease. An update. Adv Neurol. 2001;86:373-383
126. Hoglinger GU, Rizk P, Muriel MP et al. Dopamine depletion impairsprecursor cell proliferation in Parkinson disease. Nat Neurosci. 2004;7:726-735
127. Monje M, Toda H, Palmer TD. In?ammatory Blockade Restores Adult Hippocampal Neurogenesis. Science. 2003;302:1760-1764
128. Butovsky O, Ziv Y, Schwartz A et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31:149-160
129. Fisher RS, van Emde Boas W, Blume W et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005;46:470-472
130. Herman ST. Single Unprovoked Seizures. Curr Treat Options Neurol. 2004;6:243-255
131. Berg AT. Risk of recurrence after a first unprovoked seizure. Epilepsia. 2008;49 Suppl 1:13-18
132. Walker MC, White HS, Sander JW. Disease modification in partial epilepsy. Brain. 2002;125:1937-1950
133. McNamara JO, Huang YZ, Leonard AS. Molecular signaling mechanisms underlying epileptogenesis. Sci STKE. 2006;2006:re12
134. Herman ST. Clinical trials for prevention of epileptogenesis. Epilepsy Res. 2006;68:35-38
135. Bertram E. The relevance of kindling for human epilepsy. Epilepsia. 2007;48 Suppl 2:65-74
136. Olsen RW, Avoli M. GABA and epileptogenesis. Epilepsia. 1997;38:399-407
137. Staley KJ, Soldo BL, Proctor WR. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science. 1995;269:977-981
138. Kopniczky Z, Dobo E, Borbely S et al. Lateral entorhinal cortex lesions rearrange afferents, glutamate receptors, increase seizure latency and suppress seizure-induced c-fos expression in the hippocampus of adult rat. J Neurochem. 2005;95:111-124
139. Leke R, Oliveira DL, Schmidt AP et al. Methotrexate induces seizure and decreases glutamate uptake in brain slices: prevention by ionotropic glutamate receptors antagonists and adenosine. Life Sci. 2006;80:1-8
140. Miyamoto M, Ishida M, Shinozaki H. Anticonvulsive and neuroprotective actions of a potent agonist (DCG-IV) for group II metabotropic glutamate receptors against intraventricular kainate in the rat. Neuroscience. 1997;77:131-140
141. Ma J, Leung LS. Metabotropic glutamate receptors in the hippocampus and nucleus accumbens are involved in generating seizure-induced hippocampal gamma waves and behavioral hyperactivity. Behav Brain Res. 2002;133:45-56
142. Menks JH, Sankar R. Paroxysmal disorders In Child Neurology. New York: Lippincott Williams &Wilking, 2002
143. Simister RJ, McLean MA, Barker GJ, Duncan JS. Proton MR spectroscopy of metabolite concentrations in temporal lobe epilepsy and effect of temporal lobe resection. Epilepsy Res. 2009;83:168-176
144. Ratzliff AH, Howard AL, Santhakumar V et al. Rapid deletion of mossy cells does not result in a hyperexcitable dentate gyrus: implications for epileptogenesis. J Neurosci. 2004;24:2259-2269
145. Obenaus A, Esclapez M, Houser CR. Loss of glutamate decarboxylase mRNA-containing neurons in the rat dentate gyrus following pilocarpine-induced seizures. J Neurosci. 1993;13:4470-4485
146. Zappone CA, Sloviter RS. Translamellar disinhibition in the rat hippocampal dentate gyrus after seizure-induced degeneration of vulnerable hilar neurons. J Neurosci. 2004;24:853-864
147. Cossart R, Esclapez M, Hirsch JC et al. GluR5 kainate receptor activation in interneurons increases tonic inhibition of pyramidal cells. Nat Neurosci. 1998;1:470-478
148. Babb TL, Pretorius JK, Kupfer WR, Crandall PH. Glutamate decarboxylase-immunoreactive neurons are preserved in human epileptic hippocampus. J Neurosci. 1989;9:2562-2574
149. Brooks-Kayal AR, Shumate MD, Jin H et al. Selective changes in single cell GABA(A) receptor subunit expression and function intemporal lobe epilepsy. Nat Med. 1998;4:1166-1172
150. White HS. Animal models of epileptogenesis. Neurology. 2002;59:S7-S14
151. Okazaki MM, Molnar P, Nadler JV. Recurrent mossy fiber pathway in rat dentate gyrus: synaptic currents evoked in presence and absence of seizure-induced growth. J Neurophysiol. 1999;81:1645-1660
152. Lothman EW, Stringer JL, Bertram EH. The dentate gyrus as a control point for seizures in the hippocampus and beyond. Epilepsy Res Suppl. 1992;7:301-313
153. Sloviter RS. Hippocampal pathology and pathophysiology in temporal lobe epilepsy. Neurologia. 1996;11 Suppl 4:29-32
154. Longo BM, Mello LE. Blockade of pilocarpine- or kainate-induced mossy fiber sprouting by cycloheximide does not prevent subsequent epileptogenesis in rats. Neurosci Lett. 1997;226:163-166
155. Araque A, Perea G. Glial modulation of synaptic transmission in culture. Glia. 2004;47:241-248
156. Bordey A, Sontheimer H. Properties of human glial cells associated with epileptic seizure foci. Epilepsy Res. 1998;32:286-303
157. Shapiro LA, Wang L, Ribak CE. Rapid astrocyte and microglial activation following pilocarpine-induced seizures in rats. Epilepsia. 2008;49 Suppl 2:33-41
158. Khurgel M, Ivy GO. Astrocytes in kindling: relevance to epileptogenesis. Epilepsy Res. 1996;26:163-175
159. Parpura V, Basarsky TA, Liu F et al. Glutamate-mediated astrocyte–neuron signalling Nature. 1994;369:744-747
160. Tian GF, Azmi H, Takano T et al. An astrocytic basis of epilepsy. Nat Med. 2005;11:973-981
161. Fellin T, Pascual O, Gobbo S et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron. 2004;43:729-743
162. Rouach N, Koulakoff A, Abudara V et al. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science.2008;322:1551-1555
163. Ravizza T, Rizzi M, Perego C et al. Inflammatory response and glia activation in developing rat hippocampus after status epilepticus. Epilepsia. 2005;46 Suppl 5:113-117
164. Kang TC, Kim DS, Kwak SE et al. Epileptogenic roles of astroglial death and regeneration in the dentate gyrus of experimental temporal lobe epilepsy. Glia. 2006;54:258-271
165. Koh S, Storey TW, Santos TC et al. Early-life seizures in rats increase susceptibility to seizure-induced brain injury in adulthood. Neurology. 1999;53:915-921
166. Zheng H, Zhu W, Zhao H et al. Kainic acid-activated microglia mediate increased excitability of rat hippocampal neurons in vitro and in vivo: crucial role of interleukin-1beta. Neuroimmunomodulation;17:31-38
167. Parent JM, Yu TW, Leibowitz RT et al. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci. 1997;17:3727-3738
168. Hattiangady B, Rao MS, Shetty AK. Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol Dis. 2004;17:473-490
169. Ekdahl CT, Mohapel P, Elmer E, Lindvall O. Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus. Eur J Neurosci. 2001;14:937-945
170. Jessberger S, Romer B, Babu H, Kempermann G. Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells. Exp Neurol. 2005;196:342-351
171. Gray WP, Sundstrom LE. Kainic acid increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat. Brain Res. 1998;790:52-59
172. Blumcke I, Schewe JC, Normann S et al. Increase of nestin-immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy.Hippocampus. 2001;11:311-321
173. Croll SD, Goodman JH, Scharfman HE. Vascular endothelial growth factor (VEGF) in seizures: a double-edged sword. Adv Exp Med Biol. 2004;548:57-68
174. Banerjee SB, Rajendran R, Dias BG et al. Recruitment of the Sonic hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesis. Eur J Neurosci. 2005;22:1570-1580
175. Howell OW, Silva S, Scharfman HE et al. Neuropeptide Y is important for basal and seizure-induced precursor cell proliferation in the hippocampus. Neurobiol Dis. 2007;26:174-188
176. Jessberger S, Nakashima K, Clemenson GD, Jr. et al. Epigenetic modulation of seizure-induced neurogenesis and cognitive decline. J Neurosci. 2007;27:5967-5975
177. Deisseroth K, Singla S, Toda H et al. Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron. 2004;42:535-552
178. Houser CR. Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res. 1990;535:195-204
179. Parent JM, Elliott RC, Pleasure SJ et al. Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy. Ann Neurol. 2006;59:81-91
180. Scharfman HE, Sollas AE, Berger RE et al. Perforant path activation of ectopic granule cells that are born after pilocarpine-induced seizures. Neuroscience. 2003;121:1017-1029
181. Pierce JP, Melton J, Punsoni M et al. Mossy fibers are the primary source of afferent input to ectopic granule cells that are born after pilocarpine-induced seizures. Exp Neurol. 2005;196:316-331
182. Scharfman HE, Goodman JH, Sollas AL. Granule-like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: functional implications of seizure-induced neurogenesis. J Neurosci. 2000;20:6144-6158
183. Shapiro LA, Korn MJ, Ribak CE. Newly generated dentate granule cells from epileptic rats exhibit elongated hilar basal dendrites thatalign along GFAP-immunolabeled processes. Neuroscience. 2005;136:823-831
184. Shapiro LA, Ribak CE. Newly born dentate granule neurons after pilocarpine-induced epilepsy have hilar basal dendrites with immature synapses. Epilepsy Res. 2006;69:53-66
185. Walter C, Murphy BL, Pun RY et al. Pilocarpine-induced seizures cause selective time-dependent changes to adult-generated hippocampal dentate granule cells. J Neurosci. 2007;27:7541-7552
186. Overstreet-Wadiche LS, Bromberg DA, Bensen AL, Westbrook GL. Seizures accelerate functional integration of adult-generated granule cells. J Neurosci. 2006;26:4095-4103
187. Arisi GM, Garcia-Cairasco N. Doublecortin-positive newly born granule cells of hippocampus have abnormal apical dendritic morphology in the pilocarpine model of temporal lobe epilepsy. Brain Res. 2007;1165:126-134
188. Jung KH, Chu K, Kim M et al. Continuous cytosine-b-D-arabinofuranoside infusion reduces ectopic granule cells in adult rat hippocampus with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Eur J Neurosci. 2004;19:3219-3226
189. Raedt R, Boon P, Persson A et al. Radiation of the rat brain suppresses seizure-induced neurogenesis and transiently enhances excitability during kindling acquisition. Epilepsia. 2007;48:1952-1963
190. Pekcec A, Muhlenhoff M, Gerardy-Schahn R, Potschka H. Impact of the PSA-NCAM system on pathophysiology in a chronic rodent model of temporal lobe epilepsy. Neurobiol Dis. 2007;27:54-66
191. Pekcec A, Fuest C, Muhlenhoff M et al. Targeting epileptogenesis-associated induction of neurogenesis by enzymatic depolysialylation of NCAM counteracts spatial learning dysfunction but fails to impact epilepsy development. J Neurochem. 2008;105:389-400
192. Kralic JE, Ledergerber DA, Fritschy JM. Disruption of the neurogenic potential of the dentate gyrus in a mouse model of temporal lobe epilepsy with focal seizures. Eur J Neurosci. 2005;22:1916-1927
193. Bonde S, Ekdahl CT, Lindvall O. Long-term neuronal replacement in adult rat hippocampus after status epilepticus despite chronic inflammation. Eur J Neurosci. 2006;23:965-974
194. Cha BH, Akman C, Silveira DC et al. Spontaneous recurrent seizure following status epilepticus enhances dentate gyrus neurogenesis. Brain Dev. 2004;26:394-397
195. Mathern GW, Leiphart JL, De Vera A et al. Seizures decrease postnatal neurogenesis and granule cell development in the human fascia dentata. Epilepsia. 2002;43 Suppl 5:68-73
196. Pirttila TJ, Manninen A, Jutila L et al. Cystatin C expression is associated with granule cell dispersion in epilepsy. Ann Neurol. 2005;58:211-223
197. Crespel A, Rigau V, Coubes P et al. Increased number of neural progenitors in human temporal lobe epilepsy. Neurobiol Dis. 2005;19:436-450
198. Fahrner A, Kann G, Flubacher A et al. Granule cell dispersion is not accompanied by enhanced neurogenesis in temporal lobe epilepsy patients. Exp Neurol. 2007;203:320-332
199. Shetty AK, Zaman V, Shetty GA. Hippocampal neurotrophin levels in a kainate model of temporal lobe epilepsy: a lack of correlation between brain-derived neurotrophic factor content and progression of aberrant dentate mossy fiber sprouting. J Neurochem. 2003;87:147-159
200. Busceti CL, Biagioni F, Aronica E et al. Induction of the Wnt inhibitor, Dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy. Epilepsia. 2007;48:694-705
201. Jakubs K, Nanobashvili A, Bonde S et al. Environment matters: synaptic properties of neurons born in the epileptic adult brain develop to reduce excitability. Neuron. 2006;52:1047-1059
202. Pauli E, Hildebrandt M, Romstock J et al. Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss. Neurology. 2006;67:1383-1389
203. Perera TD, Coplan JD, Lisanby SH et al. Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. JNeurosci. 2007;27:4894-4901
204. Lichtenwalner RJ, Forbes ME, Bennett SA et al. Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience. 2001;107:603-613
205. Jin K, Sun Y, Xie L et al. Neurogenesis and aging: FGF-2 and HB-EGF restore neurogenesis in hippocampus and subventricular zone of aged mice. Aging Cell. 2003;2:175-183
206. Denio LS, Drake ME, Jr., Pakalnis A. The effect of exercise on seizure frequency. J Med. 1989;20:171-176
207. Arida RM, Cavalheiro EA, de Albuquerque M et al. Physical exercise in epilepsy: the case in favor. Epilepsy Behav. 2007;11:478-479
208. Koh S, Magid R, Chung H et al. Depressive behavior and selective down-regulation of serotonin receptor expression after early-life seizures: reversal by environmental enrichment. Epilepsy Behav. 2007;10:26-31
209. Hattiangady B, Shuai B, Cai J et al. Increased dentate neurogenesis after grafting of glial restricted progenitors or neural stem cells in the aging hippocampus. Stem Cells. 2007;25:2104-2117
210. Shetty AK, Hattiangady B. Concise review: prospects of stem cell therapy for temporal lobe epilepsy. Stem Cells. 2007;25:2396-2407
211. Parent JM, Lowenstein DH. Mossy fiber reorganization in the epileptic hippocampus. Curr Opin Neurol. 1997;10:103-109
212. Yang F, Wang JC, Han JL et al. Different effects of mild and severe seizures on hippocampal neurogenesis in adult rats. Hippocampus. 2008;18:460-468
213. Francis F, Koulakoff A, Boucher D et al. Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron. 1999;23:247-256
214. Gleeson JG, Lin PT, Flanagan LA, Walsh CA. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron. 1999;23:257-271
215. Lendahl U, Zimmerman LB, McKay RD. CNS stem cells express anew class of intermediate filament protein. Cell. 1990;60:585-595
216. Scorza CA, Arida RM, Cavalheiro EA et al. Expression of nestin in the hippocampal formation of rats submitted to the pilocarpine model of epilepsy. Neurosci Res. 2005;51:285-291
217. Arvidsson A, Collin T, Kirik D et al. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002;8:963-970
218. Iwai M, Sato K, Kamada H et al. Temporal profile of stem cell division, migration, and differentiation from subventricular zone to olfactory bulb after transient forebrain ischemia in gerbils. J Cereb Blood Flow Metab. 2003;23:331-341
219. Raper JA. Semaphorins and their receptors in vertebrates and invertebrates. Curr Opin Neurobiol. 2000;10:88-94
220. Klein R. Excitatory Eph receptors and adhesive ephrin ligands. Curr Opin Cell Biol. 2001;13:196-203
221. Song H, Poo M. The cell biology of neuronal navigation. Nat Cell Biol. 2001;3:E81-88
222. Wong K, Park HT, Wu JY, Rao Y. Slit proteins: molecular guidance cues for cells ranging from neurons to leukocytes. Curr Opin Genet Dev. 2002;12:583-591
223. Zhu Y, Yu T, Zhang XC et al. Role of the chemokine SDF-1 as the meningeal attractant for embryonic cerebellar neurons. Nat Neurosci. 2002;5:719-720
224. Alcantara S, Ruiz M, De Castro F et al. Netrin 1 acts as an attractive or as a repulsive cue for distinct migrating neurons during the development of the cerebellar system. Development. 2000;127:1359-1372
225. Eickholt BJ, Mackenzie SL, Graham A et al. Evidence for collapsin-1 functioning in the control of neural crest migration in both trunk and hindbrain regions. Development. 1999;126:2181-2189
226. Haas CA, Dudeck O, Kirsch M et al. Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy. J Neurosci. 2002;22:5797-5802
227. Ernfors P, Bengzon J, Kokaia Z et al. Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis. Neuron. 1991;7:165-176
228. Isackson PJ, Huntsman MM, Murray KD, Gall CM. BDNF mRNA expression is increased in adult rat forebrain after limbic seizures: temporal patterns of induction distinct from NGF. Neuron. 1991;6:937-948
229. Scharfman H, Goodman J, Macleod A et al. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol. 2005;192:348-356
230. Parent JM, Murphy GG. Mechanisms and functional significance of aberrant seizure-induced hippocampal neurogenesis. Epilepsia. 2008;49:19-25
231. Jorgensen MB, Finsen BR, Jensen MB et al. Microglial and astroglial reactions to ischemic and kainic acid-induced lesions of the adult rat hippocampus. Exp Neurol. 1993;120:70-88
232. Shapiro LA, Wang L, Ribak CE. Rapid astrocyte and microglial activation following pilocarpine-induced seizures in rats. Epilepsia. 2008;49:33-41
233. Hatten ME, Liem RK, Shelanski ML, Mason CA. Astroglia in CNS injury. Glia. 1991;4:233-243
234. Menet V, Gimenez y Ribotta M, Chauvet N et al. Inactivation of the glial fibrillary acidic protein gene, but not that of vimentin, improves neuronal survival and neurite growth by modifying adhesion molecule expression. J Neurosci. 2001;21:6147-6158
235. Shapiro LA, Korn MJ, Ribak CE. Newly Generated Dentate Granule Cells From Epileptic Rats Exhibit Elongated Hilar Basal Dendrites That Align Along GFAP-Immunolabeled Processes. Neurosci Lett. 2005;136:823-831
236. Farber K, Kettenmann H. Physiology of microglial cells. Brain Res Brain Res Rev. 2005;48:133-143
237. Aarum J, Sandberg K, Haeberlein S, Persson M. Migration and differentiation of neural precursor cells can be directed by microglia. Proc Natl Acad Sci U S A. 2003;100:15983-15988
238. Paulsen RE, Contestablie A, Villani L, Fonnum F. An in vivo model for studying function of brain tissue temporarily devoid of glial cell metabolism: the use of fluorocitrate. J. Neurochem. 1987; 48:1377-1385
239. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 5th ed: Elsevier Academic Press, 2005
240. Lian XY, Stringer JL. Astrocytes contribute to regulation of extracellular calcium and potassium in the rat cerebral cortex during spreading depression. Brain Res. 2004;1012:177-184
241. Stringer JL, Aribi AM. Effects of glial toxins on extracellular acidification in the hippocampal CA1 region in vivo. Epilepsy Res. 2003;54:163-170
242. Tikka T, Fiebich BL, Goldsteins G et al. Minocycline, a Tetracycline Derivative, Is Neuroprotective against Excitotoxicity by Inhibiting Activation and Proliferation of Microglia. J Neurosci. 2001;21:2580-2588
243. Brundula V, Rewcastle NB, Metz LM et al. Targeting leukocyte MMPs and transmigration: Minocycline as a potential therapy for multiple sclerosis. Brain. 2002;125:1297-1308
244. Schmued LC, Hopkins KJ. Fluoro-Jade: novel fluorochromes for detecting toxicant-induced neuronal degeneration. Toxicol Pathol. 2000;28:91-99
245. Jessberger S, Nakashima K, Clemenson GDJ et al. Epigenetic Modulation of Seizure-Induced Neurogenesis and Cognitive Decline. J Neurosci. 2007;27:5967-5975
246. Badan I, Buchhold B, Hamm A et al. Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery. J Cereb Blood Flow Metab. 2003;23:845-854
247. Gwag BJ, Sessler FM, Robine V, Springer JE. Endogenous glutamate levels regulate nerve growth factor mRNA expression in the rat dentate gyrus. Mol Cell. 1997;7:425-430
248. Stringer JL, Mukherjee K, Xiang T, Xu K. Regulation of extracellular calcium in the hippocampus in vivo during epileptiform activity-role of astrocytes. Epilepsy Res. 2007;74:155-162
249. Ekdahl C, Claasen J, Bonde S et al. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100:13632-13637
250. Ding S, Fellin T, Zhu Y et al. Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus. J Neurosci. 2007;27:10674-10684
251. Fellin T, Pascual O, Gobbo S et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron. 2004;43:729-743
252. Liang J, Takeuchi H, Doi Y et al. Excitatory amino acid transporter expression by astrocytes is neuroprotective against microglial excitotoxicity. Brain Res. 2008;1210:11-19
253. Weller ML, Stone IM, Goss A et al. Selective overexpression of excitatory amino acid transporter 2 (EAAT2) in astrocytes enhances neuroprotection from moderate but not severe hypoxia-ischemia. Neuroscience. 2008;155:1204-1211
254. Madrigal JL, Leza JC, Polak P et al. Astrocyte-derived MCP-1 mediates neuroprotective effects of noradrenaline. J Neurosci. 2009;29:263-267
255. Clarke DD. Fluoroacetate and Fluorocitrate: Mechanism of Action. Neurochem Res. 1991;16:1055-1058
256. Fonnum F, Johnsen A, Hassel B. Use of fluorocitrate and fluoroacetate in study of brain metabolism. Glia. 1997;21:106-113
257. Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther. 2003;304:1-7
258. Streit WJ, Walter SA, Pennell NA. Reactive microgliosis. Prog Neurobiol 1999;57:563-581
259. Rappold PM, Lynd-Balta E, Joseph SA. P2X7 receptor immunoreactive profile confined to resting and activated microglia in the epileptic brain. Brain Res. 2006;1089:171-178
260. Takeuchi H, Mizuno T, Zhang G et al. Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction towardneuronal death by inhibition of mitochondrial respiration and axonal transport. J Biol Chem. 2005;280:10444-10454
261. Turrin NP, Rivest S. Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy. Neurobiol Dis. 2004;16:321-334
262. Sun L, Lee J, Fine HA. Neuronally expressed stem cell factor induces neural stem cell migration to areas of brain injury. J Clin Invest. 2004;113:1364-1374
263. Scharfman HE, Goodman JH, Macleod A et al. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol. 2005;192:348-356
264. Cameron HA, McKay RD. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol. 2001;435:406-417
265. Liu S, Wang J, Zhu D et al. Generation of functional inhibitory neurons in the adult rat hippocampus. J Neurosci. 2003;23:732-736
266. Sperk G, Furtinger S, Schwarzer C, Pirker S. GABA and its receptors in epilepsy. Adv Exp Med Biol. 2004;548:92-103
267. Soghomonian JJ, Martin DL. Two isoforms of glutamate decarboxylase: why? Trends Pharmacol Sci. 1998;19:500-505
268. Esclapez M, Tillakaratne NJ, Kaufman DL et al. Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms. J Neurosci. 1994;14:1834-1855
269. Tamamaki N, Yanagawa Y, Tomioka R et al. Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J Comp Neurol. 2003;467:60-79
270. Doi T, Ueda Y, Nagatomo K, Willmore LJ. Role of glutamate and GABA transporters in development of pentylenetetrazol-kindling. Neurochem Res. 2009;34:1324-1331
271. Curia G, Longo D, Biagini G et al. The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods. 2008;172:143-157
272. Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol. 1972;32:281-294
273. Jiang W, Wan Q, Zhang ZJ et al. Dentate granule cell neurogenesis after seizures induced by pentylenetrazol in rats. Brain Res. 2003;977:141-148
274. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20:9104-9110
275. Ali A, Ahmad FJ, Pillai KK, Vohora D. Amiloride protects against pentylenetetrazole-induced kindling in mice. Br J Pharmacol. 2005;145:880-884
276. Sloviter RS. Status epilepticus-induced neuronal injury and network reorganization. Epilepsia. 1999;40 Suppl 1:S34-39; discussion S40-31
277. Yin J, Ma Y, Yin Q et al. Involvement of over-expressed BMP4 in pentylenetetrazol kindling-induced cell proliferation in the dentate gyrus of adult rats. Biochem Biophys Res Commun. 2007;355:54-60
278. Dayer AG, Ford AA, Cleaver KM et al. Short-term and long-term survival of new neurons in the rat dentate gyrus. J Comp Neurol. 2003;460:563-572
279. Mohapel P, Ekdahl CT, Lindvall O. Status epilepticus severity influences the long-term outcome of neurogenesis in the adult dentate gyrus. Neurobiol Dis. 2004;15:196-205
280. Huttmann K, Sadgrove M, Wallraff A et al. Seizures preferentially stimulate proliferation of radial glia-like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis. Eur J Neurosci. 2003;18:2769-2778
281. Ekdahl CT, Zhu C, Bonde S et al. Death mechanisms in status epilepticus-generated neurons and effects of additional seizures on their survival. Neurobiol Dis. 2003;14:513-523
282. Sloviter RS, Dichter MA, Rachinsky TL et al. Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus. J Comp Neurol. 1996;373:593-618
283. Schwarzer C, Sperk G. Hippocampal granule cells express glutamic acid decarboxylase-67 after limbic seizures in the rat. Neuroscience. 1995;69:705-709
284. Walker MC, Ruiz A, Kullmann DM. Monosynaptic GABAergic signaling from dentate to CA3 with a pharmacological and physiological profile typical of mossy fiber synapses. Neuron. 2001;29:703-715
285. Gutierrez R, Romo-Parra H, Maqueda J et al. Plasticity of the GABAergic phenotype of the "glutamatergic" granule cells of the rat dentate gyrus. J Neurosci. 2003;23:5594-5598
286. Gomez-Lira G, Lamas M, Romo-Parra H, Gutierrez R. Programmed and induced phenotype of the hippocampal granule cells. J Neurosci. 2005;25:6939-6946
287. Gutierrez R, Heinemann U. Co-existence of GABA and Glu in the hippocampal granule cells: implications for epilepsy. Curr Top Med Chem. 2006;6:975-978
288. Paulsen O, Moser EI. A model of hippocampal memory encoding and retrieval: GABAergic control of synaptic plasticity. Trends Neurosci. 1998;21:273-278
289. Noebels JL. The biology of epilepsy genes. Annu Rev Neurosci. 2003;26:599-625
2. Ramon y Cajal S. Texture of the Nervous System of Man and Vertebrates (Trans. Pasik, P. & Pasik, T., from the 1899-1904 Spanish adn): Springer, Vienna, 1999
3. Ramon y Cajal S. Degeneration and Regeneration of the Neuvous System (Trans. Day, R.M., From the 1913 Spanish edn): Oxford Univ. Press, London, 1928
4. Jacobson M. Development Neurobiology: Holt, Rinehart, and Winston, New York, 1970
5. Altman J. Autoradiographic investigation of cell proliferation in the brains of rats and cats. Anat Rec. 1963;145:573-591
6. Altman J. Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol. 1969;137:433-457
7. Kaplan MS, Hinds JW. Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science. 1977;197:1092-1094
8. Rakic P. Limits of neurogenesis in primates. Science. 1985;227:1054-1056
9. Alvarez-Buylla A, Nottebohm F. Migration of young neurons in adult avian brain. Nature. 1988;335:353-354
10. Alvarez-Buylla A, Theelen M, Nottebohm F. Birth of projection neurons in the higher vocal center of the canary forebrain before, during, and after song learning. Proc Natl Acad Sci U S A. 1988;85:8722-8726
11. Burd GD, Nottebohm F. Ultrastructural characterization of synaptic terminals formed on newly generated neurons in a song control nucleus of the adult canary forebrain. J Comp Neurol. 1985;240:143-152
12. Paton JA, Nottebohm FN. Neurons generated in the adult brain are recruited into functional circuits. Science. 1984;225:1046-1048
13. Gould E, Cameron HA, Daniels DC et al. Adrenal hormones suppress cell division in the adult rat dentate gyrus. J Neurosci. 1992;12:3642-3650
14. Cameron HA, Woolley CS, McEwen BS, Gould E. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience. 1993;56:337-344
15. Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996;16:2027-2033
16. Gould E, McEwen BS, Tanapat P et al. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci. 1997;17:2492-2498
17. Gould E, Reeves AJ, Fallah M et al. Hippocampal neurogenesis in adult Old World primates. Proc Natl Acad Sci U S A. 1999;96:5263-5267
18. Kornack DR, Rakic P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci U S A. 1999;96:5768-5773
19. Eriksson PS, Perfilieva E, Bjork-Eriksson T et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4:1313-1317
20. van Praag H, Schinder AF, Christie BR et al. Functional neurogenesis in the adult hippocampus. Nature. 2002;415:1030-1034
21. Ramirez-Amaya V, Marrone DF, Gage FH et al. Integration of new neurons into functional neural networks. J Neurosci. 2006;26:12237-12241
22. Lois C, Alvarez-Buylla A. Long-distance neuronal migration in the adult mammalian brain. Science. 1994;264:1145-1148
23. Corotto FS, Henegar JR, Maruniak JA. Odor deprivation leads to reduced neurogenesis and reduced neuronal survival in the olfactory bulb of the adult mouse. Neuroscience. 1994;61:739-744
24. Bedard A, Parent A. Evidence of newly generated neurons in thehuman olfactory bulb. Brain Res Dev Brain Res. 2004;151:159-168
25. Sanai N, Tramontin AD, Quinones-Hinojosa A et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature. 2004;427:740-744
26. Curtis MA, Kam M, Nannmark U et al. Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science. 2007;315:1243-1249
27. Kaplan MS. Neurogenesis in the 3-month-old rat visual cortex. J Comp Neurol. 1981;195:323-338
28. Huang L, DeVries GJ, Bittman EL. Photoperiod regulates neuronal bromodeoxyuridine labeling in the brain of a seasonally breeding mammal. J Neurobiol. 1998;36:410-420
29. Dayer AG, Cleaver KM, Abouantoun T, Cameron HA. New GABAergic interneurons in the adult neocortex and striatum are generated from different precursors. J Cell Biol. 2005;168:415-427
30. Gould E, Reeves AJ, Graziano MS, Gross CG. Neurogenesis in the neocortex of adult primates. Science. 1999;286:548-552
31. Kodama M, Fujioka T, Duman RS. Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol Psychiatry. 2004;56:570-580
32. Ehninger D, Kempermann G. Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex. Cereb Cortex. 2003;13:845-851
33. Kornack DR, Rakic P. Cell proliferation without neurogenesis in adult primate neocortex. Science. 2001;294:2127-2130
34. Bhardwaj RD, Curtis MA, Spalding KL et al. Neocortical neurogenesis in humans is restricted to development. Proc Natl Acad Sci U S A. 2006;103:12564-12568
35. Luzzati F, De Marchis S, Fasolo A, Peretto P. Neurogenesis in the caudate nucleus of the adult rabbit. J Neurosci. 2006;26:609-621
36. Fowler CD, Johnson F, Wang Z. Estrogen regulation of cell proliferation and distribution of estrogen receptor-alpha in the brains of adult female prairie and meadow voles. J Comp Neurol.2005;489:166-179
37. Kokoeva MV, Yin H, Flier JS. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science. 2005;310:679-683
38. Zhao M, Momma S, Delfani K et al. Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci U S A. 2003;100:7925-7930
39. Bauer S, Hay M, Amilhon B et al. In vivo neurogenesis in the dorsal vagal complex of the adult rat brainstem. Neuroscience. 2005;130:75-90
40. Bedard A, Levesque M, Bernier PJ, Parent A. The rostral migratory stream in adult squirrel monkeys: contribution of new neurons to the olfactory tubercle and involvement of the antiapoptotic protein Bcl-2. Eur J Neurosci. 2002;16:1917-1924
41. Pekcec A, Loscher W, Potschka H. Neurogenesis in the adult rat piriform cortex. Neuroreport. 2006;17:571-574
42. Chmielnicki E, Benraiss A, Economides AN, Goldman SA. Adenovirally expressed noggin and brain-derived neurotrophic factor cooperate to induce new medium spiny neurons from resident progenitor cells in the adult striatal ventricular zone. J Neurosci. 2004;24:2133-2142
43. Park JH, Cho H, Kim H, Kim K. Repeated brief epileptic seizures by pentylenetetrazole cause neurodegeneration and promote neurogenesis in discrete brain regions of freely moving adult rats. Neuroscience. 2006;140:673-684
44. Frielingsdorf H, Schwarz K, Brundin P, Mohapel P. No evidence for new dopaminergic neurons in the adult mammalian substantia nigra. Proc Natl Acad Sci U S A. 2004;101:10177-10182
45. Gould E. How widespread is adult neurogenesis in mammals? Nat Rev Neurosci. 2007;8:481-488
46. Bonfanti L. PSA-NCAM in mammalian structural plasticity and neurogenesis. Prog Neurobiol. 2006;80:129-164
47. Poulsen FR, Blaabjerg M, Montero M, Zimmer J. Glutamate receptorantagonists and growth factors modulate dentate granule cell neurogenesis in organotypic, rat hippocampal slice cultures. Brain Res. 2005;1051:35-49
48. von Bohlen Und Halbach O. Immunohistological markers for staging neurogenesis in adult hippocampus. Cell Tissue Res. 2007;329:409-420
49. Jessberger S, Gage FH, Eisch AJ, Lagace DC. Making a neuron: Cdk5 in embryonic and adult neurogenesis. Trends Neurosci. 2009;32:575-582
50. Zhao C, Teng EM, Summers RG, Jr. et al. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci. 2006;26:3-11
51. Carpenter MB, Sutin J. Human Neuroanatomy, 8th ed: Baltimore/London: Williams & Wilkins, 1983
52. Eisch AJ, Cameron HA, Encinas JM et al. Adult neurogenesis, mental health, and mental illness: hope or hype? J Neurosci. 2008;28:11785-11791
53. Schinder AF, Gage FH. A hypothesis about the role of adult neurogenesis in hippocampal function. Physiology (Bethesda). 2004;19:253-261
54. Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol. 2000;425:479-494
55. Duan X, Kang E, Liu CY et al. Development of neural stem cell in the adult brain. Curr Opin Neurobiol. 2008;18:108-115
56. Kempermann G, Wiskott L, Gage FH. Functional significance of adult neurogenesis. Curr Opin Neurobiol. 2004;14:186-191
57. Kempermann G, Gast D, Kronenberg G et al. Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development. 2003;130:391-399
58. Stanfield BB, Trice JE. Evidence that granule cells generated in the dentate gyrus of adult rats extend axonal projections. Exp Brain Res. 1988;72:399-406
59. Markakis EA, Gage FH. Adult-generated neurons in the dentate gyrussend axonal projections to field CA3 and are surrounded by synaptic vesicles. J Comp Neurol. 1999;406:449-460
60. Alvarez-Buylla A, Lim DA. For the long run: maintaining germinal niches in the adult brain. Neuron. 2004;41:683-686
61. Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci. 2005;28:223-250
62. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008;132:645-660
63. Lie DC, Colamarino SA, Song HJ et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005;437:1370-1375
64. Bonaguidi MA, McGuire T, Hu M et al. LIF and BMP signaling generate separate and discrete types of GFAP-expressing cells. Development. 2005;132:5503-5514
65. Ueki T, Tanaka M, Yamashita K et al. A novel secretory factor, Neurogenesin-1, provides neurogenic environmental cues for neural stem cells in the adult hippocampus. J Neurosci. 2003;23:11732-11740
66. Gong C, Wang TW, Huang HS, Parent JM. Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus. J Neurosci. 2007;27:1803-1811
67. Jessberger S, Aigner S, Clemenson GD, Jr. et al. Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus. PLoS Biol. 2008;6:e272
68. Duan X, Chang JH, Ge S et al. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007;130:1146-1158
69. Ge S, Goh EL, Sailor KA et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature. 2006;439:589-593
70. Breunig JJ, Silbereis J, Vaccarino FM et al. Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus. Proc Natl Acad Sci U S A. 2007;104:20558-20563
71. Ge S, Pradhan DA, Ming GL, Song H. GABA sets the tempo for activity-dependent adult neurogenesis. Trends Neurosci. 2007;30:1-8
72. Esposito MS, Piatti VC, Laplagne DA et al. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J Neurosci. 2005;25:10074-10086
73. Gould E, Tanapat P, Hastings NB, Shors TJ. Neurogenesis in adulthood: a possible role in learning. Trends Cogn Sci. 1999;3:186-192
74. Leuner B, Gould E, Shors TJ. Is there a link between adult neurogenesis and learning? Hippocampus. 2006;16:216-224
75. Sisti HM, Glass AL, Shors TJ. Neurogenesis and the spacing effect: learning over time enhances memory and the survival of new neurons. Learn. Mem. 2007;14:368-375
76. Drapeau E, Montaron MF, Aguerre S, Abrous DN. Learning induced survival of new neurons depends on the cognitive status of aged rats. J. Neurosci. . 2007;27:6037-6044
77. Dupret D, Fabre A, Dobrossy MD et al. Spatial learning depends on both the addition and removal of new hippocampal neurons. PLoS Biol. . 2007;5:e214
78. Dobrossy MD, Drapeau E, Aurousseau C et al. Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date. Mol. Psychiatry. 2003;8:974-982
79. Olariu A, Yamada K, Nabeshima T. Amyloid pathology and protein kinase C (PKC): possible therapeutics effects of PKC activators. J. Pharmacol. Sci. 2005;97:1-5
80. Snyder JS, Hong NS, McDonald RJ, Wojtowicz JM. A role for adult neurogenesis in spatial long-term memory. Neuroscience. 2005;130:843-852
81. Shors TJ, Miesegaes G, Beylin A et al. Neurogenesis in the adult is involved in the formation of trace memories. Nature. 2001;410:372-376
82. Saxe MD, Battaglia F, Wang JW et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc. Natl. Acad. Sci. USA. 2006;103:17501-17506
83. Winocur G, Wojtowicz JM, Sekeres M et al. Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus. 2006;16:296-304
84. Zhang C-L, Zou Y, He W et al. A role for adult TLX-positive neural stem cells in learning and behaviour. Nature. 2008;451:1004-1007
85. Mirescu C, Gould E. Stress and adult neurogenesis. Hippocampus. 2006;16:233-238
86. Shors TJ, Mathew J, Sisti HM et al. Neurogenesis and helplessness are mediated by controllability in males but not in females. Biol. Psychiatry. 2007;62: 487-495
87. Warner-Schmidt JL, Duman RS. Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus. 2006;16:239-249
88. Encinas JM, Vaahtokari A, Enikolopov G. Fluoxetine targets early progenitor cells in the adult brain. Proc Natl Acad Sci U S A. 2006;103:8233-8238
89. Santarelli L, Saxe M, Gross C et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805-809
90. Jiang W, Zhang Y, Xiao L et al. Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J Clin Invest. 2005;115:3104-3116
91. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry. 2006;59:1116-1127
92. Rossi C, Angelucci A, Costantin L et al. Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. Eur. J. Neurosci. . 2006;24:1850-1856
93. Warner-Schmidt JL, Duman RS. VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc. Natl. Acad. Sci. USA. 2007;104:4647-4652
94. Malberg JE, Platt B, Rizzo SJ et al. Increasing the levels of insulin-like growth factor-I by an IGF binding protein inhibitor producesanxiolytic and antidepressant-like effects. Neuropsychopharmacology. 2007;32:2360-2368
95. Earnheart JC, Schweizer C, Crestani F et al. GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J. Neurosci. 2007;27:3845-3854
96. Kempermann G, Gage FH. Genetic determinants of adult hippocampal neurogenesis correlate with acquisition, but not probe trial performance, in the water maze task. Eur J Neurosci. 2002;16:129-136
97. Olson AK, Eadie BD, Ernst C, Christie BR. Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus. 2006;16:250-260
98. van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999;2:266-270
99. Kee N, Teixeira CM, Wang AH, Frankland PW. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. . Nat. Neurosci. . 2007;10:355-362
100. Tashiro A, Makino H, Gage FH. Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J. Neurosci. . 2007;.27:3252-3259
101. Bruel-Jungerman E, Laroche S, Rampon C. New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur. J. Neurosci. 2005;21:513-521
102. Klempin F, Kempermann G. Adult hippocampal neurogenesis and aging. Eur. Arch. Psychiatry Clin. Neurosci. . 2007;257: 271-280
103. van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. . 2005;25:8680-8685
104. Imai F, Suzuki H, Oda J et al. Neuroprotective effect of exogenous microglia in global brain ischemia. J Cereb Blood Flow Metab. 2007;27:488-500
105. Jin K, Wang X, Xie L et al. Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci U S A. 2006;103:13198-13202
106. Tonchev AB, Yamashima T, Zhao L et al. Proliferation of neural and neuronal progenitors after global brain ischemia in young adult macaque monkeys. Mol Cell Neurosci. 2003;23:292-301
107. Liu J, Bartels M, Lu A, Sharp FR. Microglia/macrophages proliferate in striatum and neocortex but not in hippocampus after brief global ischemia that produces ischemic tolerance in gerbil brain. J Cereb Blood Flow Metab. 2001;21:361-373
108. Liu J, Solway K, Messing RO, Sharp FR. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci. 1998;18:7768-7778
109. Dempsey RJ, Sailor KA, Bowen KK et al. Stroke-induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: effect of exogenous IGF-1 and GDNF. J Neurochem. 2003;87:586-597
110. Zhu DY, Liu SH, Sun HS, Lu YM. Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus. J Neurosci. 2003;23:223-229
111. Naylor M, Bowen KK, Sailor KA et al. Preconditioning-induced ischemic tolerance stimulates growth factor expression and neurogenesis in adult rat hippocampus. Neurochem Int. 2005;47:565-572
112. Komitova M, Perfilieva E, Mattsson B et al. Effects of cortical ischemia and postischemic environmental enrichment on hippocampal cell genesis and differentiation in the adult rat. J Cereb Blood Flow Metab. 2002;22:852-860
113. Ninomiya M, Yamashita T, Araki N et al. Enhanced neurogenesis in the ischemic striatum following EGF-induced expansion of transit-amplifying cells in the subventricular zone. Neurosci Lett. 2006;403:63-67
114. Jin K, Mao XO, Sun Y et al. Heparin-binding epidermal growth factor-like growth factor: hypoxia-inducible expression in vitro and stimulation of neurogenesis in vitro and in vivo. J Neurosci. 2002;22:5365-5373
115. Yan YP, Sailor KA, Vemuganti R, Dempsey RJ. Insulin-like growth factor-1 is an endogenous mediator of focal ischemia-induced neural progenitor proliferation. Eur J Neurosci. 2006;24:45-54
116. Nakatomi H, Kuriu T, Okabe S et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell. 2002;110:429-441
117. Tureyen K, Vemuganti R, Bowen KK et al. EGF and FGF-2 infusion increases post-ischemic neural progenitor cell proliferation in the adult rat brain. Neurosurgery. 2005;57:1254-1263; discussion 1254-1263
118. Wang L, Zhang Z, Wang Y et al. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke. 2004;35:1732-1737
119. Nygren J, Kokaia M, Wieloch T. Decreased expression of brainderived neurotrophic factor in BDNF+/-. Mice is associated with enhanced recovery of motor performance and increased neuroblast number following experimental stroke. J. Neurosci. Res. 2006;84: 626–631
120. Boekhoorn K, Joels M, Lucassen PJ. Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis. 2006;24:1-14
121. Jin K, Peel AL, Mao XO et al. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004;101:343-347
122. Donovan MH, Yazdani U, Norris RD et al. Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease. J Comp Neurol. 2006;495:70-83
123. Zhang C, McNeil E, Dressler L, Siman R. Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer's disease. Exp Neurol. 2007;204:77-87
124. Pillon B, Ertle S, Deweer B et al. Memory for spatial location in 'de novo' parkinsonian patients. Neuropsychologia. 1997;35:221-228
125. Oertel WH, Hoglinger GU, Caraceni T et al. Depression in Parkinson's disease. An update. Adv Neurol. 2001;86:373-383
126. Hoglinger GU, Rizk P, Muriel MP et al. Dopamine depletion impairsprecursor cell proliferation in Parkinson disease. Nat Neurosci. 2004;7:726-735
127. Monje M, Toda H, Palmer TD. In?ammatory Blockade Restores Adult Hippocampal Neurogenesis. Science. 2003;302:1760-1764
128. Butovsky O, Ziv Y, Schwartz A et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31:149-160
129. Fisher RS, van Emde Boas W, Blume W et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005;46:470-472
130. Herman ST. Single Unprovoked Seizures. Curr Treat Options Neurol. 2004;6:243-255
131. Berg AT. Risk of recurrence after a first unprovoked seizure. Epilepsia. 2008;49 Suppl 1:13-18
132. Walker MC, White HS, Sander JW. Disease modification in partial epilepsy. Brain. 2002;125:1937-1950
133. McNamara JO, Huang YZ, Leonard AS. Molecular signaling mechanisms underlying epileptogenesis. Sci STKE. 2006;2006:re12
134. Herman ST. Clinical trials for prevention of epileptogenesis. Epilepsy Res. 2006;68:35-38
135. Bertram E. The relevance of kindling for human epilepsy. Epilepsia. 2007;48 Suppl 2:65-74
136. Olsen RW, Avoli M. GABA and epileptogenesis. Epilepsia. 1997;38:399-407
137. Staley KJ, Soldo BL, Proctor WR. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science. 1995;269:977-981
138. Kopniczky Z, Dobo E, Borbely S et al. Lateral entorhinal cortex lesions rearrange afferents, glutamate receptors, increase seizure latency and suppress seizure-induced c-fos expression in the hippocampus of adult rat. J Neurochem. 2005;95:111-124
139. Leke R, Oliveira DL, Schmidt AP et al. Methotrexate induces seizure and decreases glutamate uptake in brain slices: prevention by ionotropic glutamate receptors antagonists and adenosine. Life Sci. 2006;80:1-8
140. Miyamoto M, Ishida M, Shinozaki H. Anticonvulsive and neuroprotective actions of a potent agonist (DCG-IV) for group II metabotropic glutamate receptors against intraventricular kainate in the rat. Neuroscience. 1997;77:131-140
141. Ma J, Leung LS. Metabotropic glutamate receptors in the hippocampus and nucleus accumbens are involved in generating seizure-induced hippocampal gamma waves and behavioral hyperactivity. Behav Brain Res. 2002;133:45-56
142. Menks JH, Sankar R. Paroxysmal disorders In Child Neurology. New York: Lippincott Williams &Wilking, 2002
143. Simister RJ, McLean MA, Barker GJ, Duncan JS. Proton MR spectroscopy of metabolite concentrations in temporal lobe epilepsy and effect of temporal lobe resection. Epilepsy Res. 2009;83:168-176
144. Ratzliff AH, Howard AL, Santhakumar V et al. Rapid deletion of mossy cells does not result in a hyperexcitable dentate gyrus: implications for epileptogenesis. J Neurosci. 2004;24:2259-2269
145. Obenaus A, Esclapez M, Houser CR. Loss of glutamate decarboxylase mRNA-containing neurons in the rat dentate gyrus following pilocarpine-induced seizures. J Neurosci. 1993;13:4470-4485
146. Zappone CA, Sloviter RS. Translamellar disinhibition in the rat hippocampal dentate gyrus after seizure-induced degeneration of vulnerable hilar neurons. J Neurosci. 2004;24:853-864
147. Cossart R, Esclapez M, Hirsch JC et al. GluR5 kainate receptor activation in interneurons increases tonic inhibition of pyramidal cells. Nat Neurosci. 1998;1:470-478
148. Babb TL, Pretorius JK, Kupfer WR, Crandall PH. Glutamate decarboxylase-immunoreactive neurons are preserved in human epileptic hippocampus. J Neurosci. 1989;9:2562-2574
149. Brooks-Kayal AR, Shumate MD, Jin H et al. Selective changes in single cell GABA(A) receptor subunit expression and function intemporal lobe epilepsy. Nat Med. 1998;4:1166-1172
150. White HS. Animal models of epileptogenesis. Neurology. 2002;59:S7-S14
151. Okazaki MM, Molnar P, Nadler JV. Recurrent mossy fiber pathway in rat dentate gyrus: synaptic currents evoked in presence and absence of seizure-induced growth. J Neurophysiol. 1999;81:1645-1660
152. Lothman EW, Stringer JL, Bertram EH. The dentate gyrus as a control point for seizures in the hippocampus and beyond. Epilepsy Res Suppl. 1992;7:301-313
153. Sloviter RS. Hippocampal pathology and pathophysiology in temporal lobe epilepsy. Neurologia. 1996;11 Suppl 4:29-32
154. Longo BM, Mello LE. Blockade of pilocarpine- or kainate-induced mossy fiber sprouting by cycloheximide does not prevent subsequent epileptogenesis in rats. Neurosci Lett. 1997;226:163-166
155. Araque A, Perea G. Glial modulation of synaptic transmission in culture. Glia. 2004;47:241-248
156. Bordey A, Sontheimer H. Properties of human glial cells associated with epileptic seizure foci. Epilepsy Res. 1998;32:286-303
157. Shapiro LA, Wang L, Ribak CE. Rapid astrocyte and microglial activation following pilocarpine-induced seizures in rats. Epilepsia. 2008;49 Suppl 2:33-41
158. Khurgel M, Ivy GO. Astrocytes in kindling: relevance to epileptogenesis. Epilepsy Res. 1996;26:163-175
159. Parpura V, Basarsky TA, Liu F et al. Glutamate-mediated astrocyte–neuron signalling Nature. 1994;369:744-747
160. Tian GF, Azmi H, Takano T et al. An astrocytic basis of epilepsy. Nat Med. 2005;11:973-981
161. Fellin T, Pascual O, Gobbo S et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron. 2004;43:729-743
162. Rouach N, Koulakoff A, Abudara V et al. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science.2008;322:1551-1555
163. Ravizza T, Rizzi M, Perego C et al. Inflammatory response and glia activation in developing rat hippocampus after status epilepticus. Epilepsia. 2005;46 Suppl 5:113-117
164. Kang TC, Kim DS, Kwak SE et al. Epileptogenic roles of astroglial death and regeneration in the dentate gyrus of experimental temporal lobe epilepsy. Glia. 2006;54:258-271
165. Koh S, Storey TW, Santos TC et al. Early-life seizures in rats increase susceptibility to seizure-induced brain injury in adulthood. Neurology. 1999;53:915-921
166. Zheng H, Zhu W, Zhao H et al. Kainic acid-activated microglia mediate increased excitability of rat hippocampal neurons in vitro and in vivo: crucial role of interleukin-1beta. Neuroimmunomodulation;17:31-38
167. Parent JM, Yu TW, Leibowitz RT et al. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci. 1997;17:3727-3738
168. Hattiangady B, Rao MS, Shetty AK. Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol Dis. 2004;17:473-490
169. Ekdahl CT, Mohapel P, Elmer E, Lindvall O. Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus. Eur J Neurosci. 2001;14:937-945
170. Jessberger S, Romer B, Babu H, Kempermann G. Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells. Exp Neurol. 2005;196:342-351
171. Gray WP, Sundstrom LE. Kainic acid increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat. Brain Res. 1998;790:52-59
172. Blumcke I, Schewe JC, Normann S et al. Increase of nestin-immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy.Hippocampus. 2001;11:311-321
173. Croll SD, Goodman JH, Scharfman HE. Vascular endothelial growth factor (VEGF) in seizures: a double-edged sword. Adv Exp Med Biol. 2004;548:57-68
174. Banerjee SB, Rajendran R, Dias BG et al. Recruitment of the Sonic hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesis. Eur J Neurosci. 2005;22:1570-1580
175. Howell OW, Silva S, Scharfman HE et al. Neuropeptide Y is important for basal and seizure-induced precursor cell proliferation in the hippocampus. Neurobiol Dis. 2007;26:174-188
176. Jessberger S, Nakashima K, Clemenson GD, Jr. et al. Epigenetic modulation of seizure-induced neurogenesis and cognitive decline. J Neurosci. 2007;27:5967-5975
177. Deisseroth K, Singla S, Toda H et al. Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron. 2004;42:535-552
178. Houser CR. Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res. 1990;535:195-204
179. Parent JM, Elliott RC, Pleasure SJ et al. Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy. Ann Neurol. 2006;59:81-91
180. Scharfman HE, Sollas AE, Berger RE et al. Perforant path activation of ectopic granule cells that are born after pilocarpine-induced seizures. Neuroscience. 2003;121:1017-1029
181. Pierce JP, Melton J, Punsoni M et al. Mossy fibers are the primary source of afferent input to ectopic granule cells that are born after pilocarpine-induced seizures. Exp Neurol. 2005;196:316-331
182. Scharfman HE, Goodman JH, Sollas AL. Granule-like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: functional implications of seizure-induced neurogenesis. J Neurosci. 2000;20:6144-6158
183. Shapiro LA, Korn MJ, Ribak CE. Newly generated dentate granule cells from epileptic rats exhibit elongated hilar basal dendrites thatalign along GFAP-immunolabeled processes. Neuroscience. 2005;136:823-831
184. Shapiro LA, Ribak CE. Newly born dentate granule neurons after pilocarpine-induced epilepsy have hilar basal dendrites with immature synapses. Epilepsy Res. 2006;69:53-66
185. Walter C, Murphy BL, Pun RY et al. Pilocarpine-induced seizures cause selective time-dependent changes to adult-generated hippocampal dentate granule cells. J Neurosci. 2007;27:7541-7552
186. Overstreet-Wadiche LS, Bromberg DA, Bensen AL, Westbrook GL. Seizures accelerate functional integration of adult-generated granule cells. J Neurosci. 2006;26:4095-4103
187. Arisi GM, Garcia-Cairasco N. Doublecortin-positive newly born granule cells of hippocampus have abnormal apical dendritic morphology in the pilocarpine model of temporal lobe epilepsy. Brain Res. 2007;1165:126-134
188. Jung KH, Chu K, Kim M et al. Continuous cytosine-b-D-arabinofuranoside infusion reduces ectopic granule cells in adult rat hippocampus with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Eur J Neurosci. 2004;19:3219-3226
189. Raedt R, Boon P, Persson A et al. Radiation of the rat brain suppresses seizure-induced neurogenesis and transiently enhances excitability during kindling acquisition. Epilepsia. 2007;48:1952-1963
190. Pekcec A, Muhlenhoff M, Gerardy-Schahn R, Potschka H. Impact of the PSA-NCAM system on pathophysiology in a chronic rodent model of temporal lobe epilepsy. Neurobiol Dis. 2007;27:54-66
191. Pekcec A, Fuest C, Muhlenhoff M et al. Targeting epileptogenesis-associated induction of neurogenesis by enzymatic depolysialylation of NCAM counteracts spatial learning dysfunction but fails to impact epilepsy development. J Neurochem. 2008;105:389-400
192. Kralic JE, Ledergerber DA, Fritschy JM. Disruption of the neurogenic potential of the dentate gyrus in a mouse model of temporal lobe epilepsy with focal seizures. Eur J Neurosci. 2005;22:1916-1927
193. Bonde S, Ekdahl CT, Lindvall O. Long-term neuronal replacement in adult rat hippocampus after status epilepticus despite chronic inflammation. Eur J Neurosci. 2006;23:965-974
194. Cha BH, Akman C, Silveira DC et al. Spontaneous recurrent seizure following status epilepticus enhances dentate gyrus neurogenesis. Brain Dev. 2004;26:394-397
195. Mathern GW, Leiphart JL, De Vera A et al. Seizures decrease postnatal neurogenesis and granule cell development in the human fascia dentata. Epilepsia. 2002;43 Suppl 5:68-73
196. Pirttila TJ, Manninen A, Jutila L et al. Cystatin C expression is associated with granule cell dispersion in epilepsy. Ann Neurol. 2005;58:211-223
197. Crespel A, Rigau V, Coubes P et al. Increased number of neural progenitors in human temporal lobe epilepsy. Neurobiol Dis. 2005;19:436-450
198. Fahrner A, Kann G, Flubacher A et al. Granule cell dispersion is not accompanied by enhanced neurogenesis in temporal lobe epilepsy patients. Exp Neurol. 2007;203:320-332
199. Shetty AK, Zaman V, Shetty GA. Hippocampal neurotrophin levels in a kainate model of temporal lobe epilepsy: a lack of correlation between brain-derived neurotrophic factor content and progression of aberrant dentate mossy fiber sprouting. J Neurochem. 2003;87:147-159
200. Busceti CL, Biagioni F, Aronica E et al. Induction of the Wnt inhibitor, Dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy. Epilepsia. 2007;48:694-705
201. Jakubs K, Nanobashvili A, Bonde S et al. Environment matters: synaptic properties of neurons born in the epileptic adult brain develop to reduce excitability. Neuron. 2006;52:1047-1059
202. Pauli E, Hildebrandt M, Romstock J et al. Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss. Neurology. 2006;67:1383-1389
203. Perera TD, Coplan JD, Lisanby SH et al. Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. JNeurosci. 2007;27:4894-4901
204. Lichtenwalner RJ, Forbes ME, Bennett SA et al. Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience. 2001;107:603-613
205. Jin K, Sun Y, Xie L et al. Neurogenesis and aging: FGF-2 and HB-EGF restore neurogenesis in hippocampus and subventricular zone of aged mice. Aging Cell. 2003;2:175-183
206. Denio LS, Drake ME, Jr., Pakalnis A. The effect of exercise on seizure frequency. J Med. 1989;20:171-176
207. Arida RM, Cavalheiro EA, de Albuquerque M et al. Physical exercise in epilepsy: the case in favor. Epilepsy Behav. 2007;11:478-479
208. Koh S, Magid R, Chung H et al. Depressive behavior and selective down-regulation of serotonin receptor expression after early-life seizures: reversal by environmental enrichment. Epilepsy Behav. 2007;10:26-31
209. Hattiangady B, Shuai B, Cai J et al. Increased dentate neurogenesis after grafting of glial restricted progenitors or neural stem cells in the aging hippocampus. Stem Cells. 2007;25:2104-2117
210. Shetty AK, Hattiangady B. Concise review: prospects of stem cell therapy for temporal lobe epilepsy. Stem Cells. 2007;25:2396-2407
211. Parent JM, Lowenstein DH. Mossy fiber reorganization in the epileptic hippocampus. Curr Opin Neurol. 1997;10:103-109
212. Yang F, Wang JC, Han JL et al. Different effects of mild and severe seizures on hippocampal neurogenesis in adult rats. Hippocampus. 2008;18:460-468
213. Francis F, Koulakoff A, Boucher D et al. Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron. 1999;23:247-256
214. Gleeson JG, Lin PT, Flanagan LA, Walsh CA. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron. 1999;23:257-271
215. Lendahl U, Zimmerman LB, McKay RD. CNS stem cells express anew class of intermediate filament protein. Cell. 1990;60:585-595
216. Scorza CA, Arida RM, Cavalheiro EA et al. Expression of nestin in the hippocampal formation of rats submitted to the pilocarpine model of epilepsy. Neurosci Res. 2005;51:285-291
217. Arvidsson A, Collin T, Kirik D et al. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002;8:963-970
218. Iwai M, Sato K, Kamada H et al. Temporal profile of stem cell division, migration, and differentiation from subventricular zone to olfactory bulb after transient forebrain ischemia in gerbils. J Cereb Blood Flow Metab. 2003;23:331-341
219. Raper JA. Semaphorins and their receptors in vertebrates and invertebrates. Curr Opin Neurobiol. 2000;10:88-94
220. Klein R. Excitatory Eph receptors and adhesive ephrin ligands. Curr Opin Cell Biol. 2001;13:196-203
221. Song H, Poo M. The cell biology of neuronal navigation. Nat Cell Biol. 2001;3:E81-88
222. Wong K, Park HT, Wu JY, Rao Y. Slit proteins: molecular guidance cues for cells ranging from neurons to leukocytes. Curr Opin Genet Dev. 2002;12:583-591
223. Zhu Y, Yu T, Zhang XC et al. Role of the chemokine SDF-1 as the meningeal attractant for embryonic cerebellar neurons. Nat Neurosci. 2002;5:719-720
224. Alcantara S, Ruiz M, De Castro F et al. Netrin 1 acts as an attractive or as a repulsive cue for distinct migrating neurons during the development of the cerebellar system. Development. 2000;127:1359-1372
225. Eickholt BJ, Mackenzie SL, Graham A et al. Evidence for collapsin-1 functioning in the control of neural crest migration in both trunk and hindbrain regions. Development. 1999;126:2181-2189
226. Haas CA, Dudeck O, Kirsch M et al. Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy. J Neurosci. 2002;22:5797-5802
227. Ernfors P, Bengzon J, Kokaia Z et al. Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis. Neuron. 1991;7:165-176
228. Isackson PJ, Huntsman MM, Murray KD, Gall CM. BDNF mRNA expression is increased in adult rat forebrain after limbic seizures: temporal patterns of induction distinct from NGF. Neuron. 1991;6:937-948
229. Scharfman H, Goodman J, Macleod A et al. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol. 2005;192:348-356
230. Parent JM, Murphy GG. Mechanisms and functional significance of aberrant seizure-induced hippocampal neurogenesis. Epilepsia. 2008;49:19-25
231. Jorgensen MB, Finsen BR, Jensen MB et al. Microglial and astroglial reactions to ischemic and kainic acid-induced lesions of the adult rat hippocampus. Exp Neurol. 1993;120:70-88
232. Shapiro LA, Wang L, Ribak CE. Rapid astrocyte and microglial activation following pilocarpine-induced seizures in rats. Epilepsia. 2008;49:33-41
233. Hatten ME, Liem RK, Shelanski ML, Mason CA. Astroglia in CNS injury. Glia. 1991;4:233-243
234. Menet V, Gimenez y Ribotta M, Chauvet N et al. Inactivation of the glial fibrillary acidic protein gene, but not that of vimentin, improves neuronal survival and neurite growth by modifying adhesion molecule expression. J Neurosci. 2001;21:6147-6158
235. Shapiro LA, Korn MJ, Ribak CE. Newly Generated Dentate Granule Cells From Epileptic Rats Exhibit Elongated Hilar Basal Dendrites That Align Along GFAP-Immunolabeled Processes. Neurosci Lett. 2005;136:823-831
236. Farber K, Kettenmann H. Physiology of microglial cells. Brain Res Brain Res Rev. 2005;48:133-143
237. Aarum J, Sandberg K, Haeberlein S, Persson M. Migration and differentiation of neural precursor cells can be directed by microglia. Proc Natl Acad Sci U S A. 2003;100:15983-15988
238. Paulsen RE, Contestablie A, Villani L, Fonnum F. An in vivo model for studying function of brain tissue temporarily devoid of glial cell metabolism: the use of fluorocitrate. J. Neurochem. 1987; 48:1377-1385
239. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 5th ed: Elsevier Academic Press, 2005
240. Lian XY, Stringer JL. Astrocytes contribute to regulation of extracellular calcium and potassium in the rat cerebral cortex during spreading depression. Brain Res. 2004;1012:177-184
241. Stringer JL, Aribi AM. Effects of glial toxins on extracellular acidification in the hippocampal CA1 region in vivo. Epilepsy Res. 2003;54:163-170
242. Tikka T, Fiebich BL, Goldsteins G et al. Minocycline, a Tetracycline Derivative, Is Neuroprotective against Excitotoxicity by Inhibiting Activation and Proliferation of Microglia. J Neurosci. 2001;21:2580-2588
243. Brundula V, Rewcastle NB, Metz LM et al. Targeting leukocyte MMPs and transmigration: Minocycline as a potential therapy for multiple sclerosis. Brain. 2002;125:1297-1308
244. Schmued LC, Hopkins KJ. Fluoro-Jade: novel fluorochromes for detecting toxicant-induced neuronal degeneration. Toxicol Pathol. 2000;28:91-99
245. Jessberger S, Nakashima K, Clemenson GDJ et al. Epigenetic Modulation of Seizure-Induced Neurogenesis and Cognitive Decline. J Neurosci. 2007;27:5967-5975
246. Badan I, Buchhold B, Hamm A et al. Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery. J Cereb Blood Flow Metab. 2003;23:845-854
247. Gwag BJ, Sessler FM, Robine V, Springer JE. Endogenous glutamate levels regulate nerve growth factor mRNA expression in the rat dentate gyrus. Mol Cell. 1997;7:425-430
248. Stringer JL, Mukherjee K, Xiang T, Xu K. Regulation of extracellular calcium in the hippocampus in vivo during epileptiform activity-role of astrocytes. Epilepsy Res. 2007;74:155-162
249. Ekdahl C, Claasen J, Bonde S et al. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100:13632-13637
250. Ding S, Fellin T, Zhu Y et al. Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus. J Neurosci. 2007;27:10674-10684
251. Fellin T, Pascual O, Gobbo S et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron. 2004;43:729-743
252. Liang J, Takeuchi H, Doi Y et al. Excitatory amino acid transporter expression by astrocytes is neuroprotective against microglial excitotoxicity. Brain Res. 2008;1210:11-19
253. Weller ML, Stone IM, Goss A et al. Selective overexpression of excitatory amino acid transporter 2 (EAAT2) in astrocytes enhances neuroprotection from moderate but not severe hypoxia-ischemia. Neuroscience. 2008;155:1204-1211
254. Madrigal JL, Leza JC, Polak P et al. Astrocyte-derived MCP-1 mediates neuroprotective effects of noradrenaline. J Neurosci. 2009;29:263-267
255. Clarke DD. Fluoroacetate and Fluorocitrate: Mechanism of Action. Neurochem Res. 1991;16:1055-1058
256. Fonnum F, Johnsen A, Hassel B. Use of fluorocitrate and fluoroacetate in study of brain metabolism. Glia. 1997;21:106-113
257. Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther. 2003;304:1-7
258. Streit WJ, Walter SA, Pennell NA. Reactive microgliosis. Prog Neurobiol 1999;57:563-581
259. Rappold PM, Lynd-Balta E, Joseph SA. P2X7 receptor immunoreactive profile confined to resting and activated microglia in the epileptic brain. Brain Res. 2006;1089:171-178
260. Takeuchi H, Mizuno T, Zhang G et al. Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction towardneuronal death by inhibition of mitochondrial respiration and axonal transport. J Biol Chem. 2005;280:10444-10454
261. Turrin NP, Rivest S. Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy. Neurobiol Dis. 2004;16:321-334
262. Sun L, Lee J, Fine HA. Neuronally expressed stem cell factor induces neural stem cell migration to areas of brain injury. J Clin Invest. 2004;113:1364-1374
263. Scharfman HE, Goodman JH, Macleod A et al. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol. 2005;192:348-356
264. Cameron HA, McKay RD. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol. 2001;435:406-417
265. Liu S, Wang J, Zhu D et al. Generation of functional inhibitory neurons in the adult rat hippocampus. J Neurosci. 2003;23:732-736
266. Sperk G, Furtinger S, Schwarzer C, Pirker S. GABA and its receptors in epilepsy. Adv Exp Med Biol. 2004;548:92-103
267. Soghomonian JJ, Martin DL. Two isoforms of glutamate decarboxylase: why? Trends Pharmacol Sci. 1998;19:500-505
268. Esclapez M, Tillakaratne NJ, Kaufman DL et al. Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms. J Neurosci. 1994;14:1834-1855
269. Tamamaki N, Yanagawa Y, Tomioka R et al. Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J Comp Neurol. 2003;467:60-79
270. Doi T, Ueda Y, Nagatomo K, Willmore LJ. Role of glutamate and GABA transporters in development of pentylenetetrazol-kindling. Neurochem Res. 2009;34:1324-1331
271. Curia G, Longo D, Biagini G et al. The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods. 2008;172:143-157
272. Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol. 1972;32:281-294
273. Jiang W, Wan Q, Zhang ZJ et al. Dentate granule cell neurogenesis after seizures induced by pentylenetrazol in rats. Brain Res. 2003;977:141-148
274. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20:9104-9110
275. Ali A, Ahmad FJ, Pillai KK, Vohora D. Amiloride protects against pentylenetetrazole-induced kindling in mice. Br J Pharmacol. 2005;145:880-884
276. Sloviter RS. Status epilepticus-induced neuronal injury and network reorganization. Epilepsia. 1999;40 Suppl 1:S34-39; discussion S40-31
277. Yin J, Ma Y, Yin Q et al. Involvement of over-expressed BMP4 in pentylenetetrazol kindling-induced cell proliferation in the dentate gyrus of adult rats. Biochem Biophys Res Commun. 2007;355:54-60
278. Dayer AG, Ford AA, Cleaver KM et al. Short-term and long-term survival of new neurons in the rat dentate gyrus. J Comp Neurol. 2003;460:563-572
279. Mohapel P, Ekdahl CT, Lindvall O. Status epilepticus severity influences the long-term outcome of neurogenesis in the adult dentate gyrus. Neurobiol Dis. 2004;15:196-205
280. Huttmann K, Sadgrove M, Wallraff A et al. Seizures preferentially stimulate proliferation of radial glia-like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis. Eur J Neurosci. 2003;18:2769-2778
281. Ekdahl CT, Zhu C, Bonde S et al. Death mechanisms in status epilepticus-generated neurons and effects of additional seizures on their survival. Neurobiol Dis. 2003;14:513-523
282. Sloviter RS, Dichter MA, Rachinsky TL et al. Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus. J Comp Neurol. 1996;373:593-618
283. Schwarzer C, Sperk G. Hippocampal granule cells express glutamic acid decarboxylase-67 after limbic seizures in the rat. Neuroscience. 1995;69:705-709
284. Walker MC, Ruiz A, Kullmann DM. Monosynaptic GABAergic signaling from dentate to CA3 with a pharmacological and physiological profile typical of mossy fiber synapses. Neuron. 2001;29:703-715
285. Gutierrez R, Romo-Parra H, Maqueda J et al. Plasticity of the GABAergic phenotype of the "glutamatergic" granule cells of the rat dentate gyrus. J Neurosci. 2003;23:5594-5598
286. Gomez-Lira G, Lamas M, Romo-Parra H, Gutierrez R. Programmed and induced phenotype of the hippocampal granule cells. J Neurosci. 2005;25:6939-6946
287. Gutierrez R, Heinemann U. Co-existence of GABA and Glu in the hippocampal granule cells: implications for epilepsy. Curr Top Med Chem. 2006;6:975-978
288. Paulsen O, Moser EI. A model of hippocampal memory encoding and retrieval: GABAergic control of synaptic plasticity. Trends Neurosci. 1998;21:273-278
289. Noebels JL. The biology of epilepsy genes. Annu Rev Neurosci. 2003;26:599-625