Jessberger Sebastian, Nakashima Kinichi, Clemenson Gregory D, Mejia Eunice, Mathews Emily, Ure Kerstin, Ogawa Shiori, Sinton Christopher M, Gage Fred H, Hsieh Jenny
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
J Neurosci. 2007 May 30;27(22):5967-75. doi: 10.1523/JNEUROSCI.0110-07.2007.
The conceptual understanding of hippocampal function has been challenged recently by the finding that new granule cells are born throughout life in the mammalian dentate gyrus (DG). The number of newborn neurons is dynamically regulated by a variety of factors. Kainic acid-induced seizures, a rodent model of human temporal lobe epilepsy, strongly induce the proliferation of DG neurogenic progenitor cells and are also associated with long-term cognitive impairment. We show here that the antiepileptic drug valproic acid (VPA) potently blocked seizure-induced neurogenesis, an effect that appeared to be mainly mediated by inhibiting histone deacetylases (HDAC) and normalizing HDAC-dependent gene expression within the epileptic dentate area. Strikingly, the inhibition of aberrant neurogenesis protected the animals from seizure-induced cognitive impairment in a hippocampus-dependent learning task. We propose that seizure-generated granule cells have the potential to interfere with hippocampal function and contribute to cognitive impairment caused by epileptic activity within the hippocampal circuitry. Furthermore, our data indicate that the effectiveness of VPA as an antiepileptic drug may be partially explained by the HDAC-dependent inhibition of aberrant neurogenesis induced by seizure activity within the adult hippocampus.
最近，哺乳动物齿状回（DG）终生都有新的颗粒细胞生成这一发现，对海马体功能的概念性理解提出了挑战。新生神经元的数量受到多种因素的动态调节。 kainic酸诱发的癫痫发作是人类颞叶癫痫的啮齿动物模型，它强烈诱导DG神经源性祖细胞的增殖，并且还与长期认知障碍有关。我们在此表明，抗癫痫药物丙戊酸（VPA）能有效阻断癫痫发作诱导的神经发生，这种作用似乎主要是通过抑制组蛋白脱乙酰酶（HDAC）并使癫痫齿状区域内依赖HDAC的基因表达正常化来介导的。令人惊讶的是，在一项依赖海马体的学习任务中，对异常神经发生的抑制保护动物免受癫痫发作诱导的认知障碍。我们提出，癫痫发作产生的颗粒细胞有可能干扰海马体功能，并导致海马体回路内癫痫活动引起的认知障碍。此外，我们的数据表明，VPA作为抗癫痫药物的有效性可能部分归因于其对成年海马体内癫痫活动诱导的异常神经发生的HDAC依赖性抑制作用。
