慢性颞叶癫痫常合并认知功能损害，严重影响患者的生存质量，但其机制不明，多认为与神经递质失衡、海马硬化相关。5-羟色胺6受体（5-HT6R）是G蛋白偶联受体，最近已经成为改善认知功能的药物靶点。我们前期研究发现5-HT6R拮抗剂显著改善慢性颞叶癫痫大鼠的认知功能损害，进一步研究显示5-HT6R在癫痫大鼠皮层、海马表达明显增加，而在纹状体中表达无变化，其具体调控机制尚不明确。因此，本项目在前期研究基础上，应用氯化铝-匹罗卡品慢性癫痫模型，通过拮抗剂和激动剂干预，采用微透析、膜片钳、免疫化学、分子生物学等技术观察5-HT6R活性改变对痫性放电、认知功能、突触可塑性、神经递质、海马神经元丢失（自噬/凋亡/坏死）、胶质细胞增生的影响，阐明5-HT6R在癫痫合并认知功能损害中的重要作用及PKA/Fyn/Jab1、生存死亡途径的神经信号机制。研究结果将为癫痫合并认知功能损害的防治提供新的药理靶点和机制。

Cognitive impairment in patients with epilepsy is notable。Why？It is blieved to be hippocampal sclerosis and inbalance between excitability and inhibility. 5-HT6 receptor is a member of Gs-GPCR family.We firstly found that it over-expressed in epileptic cortex and hippocampus. We also found 5-HT6R antagonist(SB271046) can improve the cognitive impairment in chronic temporal epileptic model. We presume that it is related to transduction mechanism such as PKA/Fyn/Jab1. 5-HT6R targets at GABA-nergic neurons and GAGA(A) receptor on glial cells. Then it lessens the loss of neurons and proliferation of glail cells, meanwhile moderates the balance between excitability and inhibility. To verify the above hypothesis,LiCL-pilocarpin induced chronic epileptic model is made. And we continue to observe whether SB-271046 and E-6801 decrease seizures and improve cognition.Then we detect neurotransmitters( such as 5-HT ,GABA,Ach,Glu )from different brain areas,the expression of 5-HT6 receptor,the co-localiztion of GABA or Glutamat-nergic neurons or glial cells,the expression of GABA(A) receptor, and the downstream signaling molecule of different transduction mechanisms.Finally,LTP and LTD also detected in vitro to elucidate how 5-HT receptor act on epilepsy accompanied with cognitive impairment.That would be worthwhile to explore new anticonvulsive drugs.