杏仁核中间神经元通过去抑制调控热性惊厥后颞叶癫痫的发生

There is a controversial issue of whether temporal lobe epilepsy (TLE) in adult is caused by febrile seizures (FS) in childhood, and increasing evidence suggests that they are closely related. It is known that amygdala plays an important role in the pathogenesis of TLE and the epileptogenic networks. The majority of the projecting circuitry in the networks is associated with the amygdale, consistent with the facts that majority of patients have the FS history in childhood, but there is no direct evidences indicating this correlation between them. Our preliminary results has confirmed that FS in immature Zebrafish could result in a high incidences of TLE in adult, and FS also could lead to the disinhibition of the amygdala interneurons and participates in the occurrence of TLE. The aim of this project is to take molecular biology, Optogenetic approach, electrophysiology and behavioral methods combined with in vivo and in vitro experiments, to study (1)whether TLE is closely related to FS during brain development; (2) does FS have an inhibitory effect on the interneurons of the amygdala? Is it possible to participate in the occurrence of TLE by regulating the minilocal / projection circuitry function? (3)Does FS affects the function of the amygdala through the Dlx1 transcription factor to participate in the occurrence of TLE? This study is expected to elucidate that FS regulates the occurrence of TLE by regulating the Dlx1 and disinhibition of the amygdala interneurons, and affecting the activity of minilocal / projective circuitry, which will provide new ideas for the prevention and treatment of TLE after FS and provide a new strategy for early intervention.

儿童热性惊厥（FS）是否导致颞叶癫痫（TLE）还存在争议，越来越多的证据表明两者密切相关。对TLE发作网络的研究发现，与杏仁核相关的投射环路模式占绝大多数，这与多数患者有FS病史相吻合，但仍缺少两者相关联的直接证据；同时两者相关联的机制尚未阐明。我们预实验发现斑马鱼FS致TLE成功极高，并已证实FS导致杏仁核中间神经元去抑制而参与了TLE的发生。本项目拟采用分子生物学、光遗传学、电生理学及行为学等手段，结合体内外实验，主要研究①TLE与脑发育时期FS的密切相关性；②FS对杏仁核中间神经元起去抑制调控作用，并通过调控局部/投射环路功能参与TLE的发生；③FS通过Dlx1转录因子发挥调控杏仁核功能，从而参与TLE的发生。本研究有望阐明FS通过调控杏仁核Dlx1转录因子、使中间神经元去抑制、影响局部/投射环路活动，从而调控TLE发生，将为防治FS后TLE的发生提供新思路，并为早期干预提供新靶点。

癫痫是一种常见疑难病症，儿童患者占到2/3。由于TLE与FS是否呈必然相关性还存在争议，但越来越多的证据表明儿童时期FS是TLE发病的关键因素。由于两者与遗传等多种因素相关，所以临床、哺乳动物模型研究均难以得出一致性的结论。大量研究表明杏仁核在TLE发病、TLE癫痫发作网络中均占有重要地位，与杏仁核有关的投射环路模式占多数，这与临床多数患者有儿童时期FS病史相吻合，但缺少关于杏仁核投射环路模式与FS病史相关联的直接证据。我们不仅研究了不同脑发育时期FS与成年后TLE 发生的相关性，还研究不同温度等条件对这种相关性的影响。基本明确了杏仁核中间神经元通过去抑制调控FS后TLE发生的作用及机制：不仅研究FS对杏仁核主要类型中间神经元的影响-去抑制作用，还进一步研究了对杏仁核主要类型中间神经元的作用是否影响PN神经元的信号输出，明确了局部/投射环路调控机制，最后还探讨这种调控作用是TLE 发生的关键，从而明确杏仁核中间神经元通过去抑制调控FS后TLE 发生的作用和环路调控机制。初步阐明了Dlx1、Egr1 等是调控杏仁核中间神经元参与FS 后TLE 发生的关键信号分子。本研究有望阐明FS调控杏仁核功能及其参与TLE发生的机制即通过调控杏仁核中间神经元Dlx1、Egr1等，影响局部/投射环路活动，从而调控TLE的发生，将为防治FS后TLE的发生提供新思路，并为早期干预提供新靶点，将具有重要的理论意义和应用价值。目前已发表论文10篇（SCI收录9篇,IM收录1篇），培养研究生5名，并完成了一定的学术交流。