Parent J M, Yu T W, Leibowitz R T, Geschwind D H, Sloviter R S, Lowenstein D H
Departments of Neurology and Anatomy, University of California, San Francisco, California 94143, USA.
J Neurosci. 1997 May 15;17(10):3727-38. doi: 10.1523/JNEUROSCI.17-10-03727.1997.
The dentate granule cell layer of the rodent hippocampal formation has the distinctive property of ongoing neurogenesis that continues throughout adult life. In both human temporal lobe epilepsy and rodent models of limbic epilepsy, this same neuronal population undergoes extensive remodeling, including reorganization of mossy fibers, dispersion of the granule cell layer, and the appearance of granule cells in ectopic locations within the dentate gyrus. The mechanistic basis of these abnormalities, as well as their potential relationship to dentate granule cell neurogenesis, is unknown. We used a systemic chemoconvulsant model of temporal lobe epilepsy and bromodeoxyuridine (BrdU) labeling to investigate the effects of prolonged seizures on dentate granule cell neurogenesis in adult rats, and to examine the contribution of newly differentiated dentate granule cells to the network changes seen in this model. Pilocarpine-induced status epilepticus caused a dramatic and prolonged increase in cell proliferation in the dentate subgranular proliferative zone (SGZ), an area known to contain neuronal precursor cells. Colocalization of BrdU-immunolabeled cells with the neuron-specific markers turned on after division, 64 kDa, class III beta-tubulin, or microtubule-associated protein-2 showed that the vast majority of these mitotically active cells differentiated into neurons in the granule cell layer. Newly generated dentate granule cells also appeared in ectopic locations in the hilus and inner molecular layer of the dentate gyrus. Furthermore, developing granule cells projected axons aberrantly to both the CA3 pyramidal cell region and the dentate inner molecular layer. Induction of hippocampal seizure activity by perforant path stimulation resulted in an increase in SGZ mitotic activity similar to that seen with pilocarpine administration. These observations indicate that prolonged seizure discharges stimulate dentate granule cell neurogenesis, and that hippocampal network plasticity associated with epileptogenesis may arise from aberrant connections formed by newly born dentate granule cells.
啮齿动物海马结构的齿状颗粒细胞层具有持续神经发生的独特特性，这种特性在成年期会持续存在。在人类颞叶癫痫和边缘叶癫痫的啮齿动物模型中，同样的神经元群体经历了广泛的重塑，包括苔藓纤维的重组、颗粒细胞层的分散以及齿状回异位位置出现颗粒细胞。这些异常的机制基础以及它们与齿状颗粒细胞神经发生的潜在关系尚不清楚。我们使用颞叶癫痫的全身化学惊厥模型和溴脱氧尿苷（BrdU）标记来研究成年大鼠长时间癫痫发作对齿状颗粒细胞神经发生的影响，并检查新分化的齿状颗粒细胞对该模型中所见网络变化的贡献。毛果芸香碱诱导的癫痫持续状态导致齿状颗粒下增殖区（SGZ）细胞增殖显著且持续增加，该区域已知含有神经元前体细胞。BrdU免疫标记细胞与分裂后开启的神经元特异性标记物（64 kDa、III类β-微管蛋白或微管相关蛋白-2）的共定位表明，这些有丝分裂活跃细胞中的绝大多数分化为颗粒细胞层中的神经元。新生成的齿状颗粒细胞也出现在齿状回的海马区和内分子层的异位位置。此外，发育中的颗粒细胞将轴突异常投射到CA3锥体细胞区域和齿状回内分子层。通过穿通通路刺激诱导海马癫痫活动导致SGZ有丝分裂活性增加，类似于毛果芸香碱给药后所见。这些观察结果表明，长时间的癫痫放电刺激齿状颗粒细胞神经发生，并且与癫痫发生相关的海马网络可塑性可能源于新生齿状颗粒细胞形成的异常连接。
