Temporal ontogeny of epileptogenesis in a model of adult-onset, spontaneous seizures

摘要 颞叶癫痫(TLE)是部分性癫痫最常见的形式，通常难治性 边缘结构的治疗，包括海马体，与癫痫的产生有关。一旦成为 癫痫发作时，癫痫复发的风险增加，癫痫发作本身会进一步加重 建立异常网络。即使这种癫痫发作后进展的模式在 一种点燃的动物模型，在该模型中，由化学处理引起一段时间的剧烈癫痫发作 或生理诱导，人们对导致首次癫痫发作的机制知之甚少， 尤其是在没有遗传原因或损伤的情况下出现癫痫时。点燃研究支持 癫痫诱导的海马脑源性神经营养因子(BDNF)信号增强的作用 在随后的癫痫发作的发展中，增加了正常的BDNF功能可能是 通过癫痫发作活动来重塑突触组织。我们可以推断出这种坚持不懈 BDNF调控的中断本身可能同样会重塑组织，有利于形成亲- 癫痫回路。这项应用使用了一种转基因小鼠品系，该品系在 钙/钙调蛋白依赖性激酶IIα启动子(TgBDNF)作用下的前脑损伤 研究突触回路的缓慢和渐进性重塑，标志着从正常到 没有事先点燃的癫痫脑。部分TgBDNF小鼠出现自发性癫痫发作 随着老鼠数量的增加，成年中期对提尾和笼子抖动的反应 随着年龄的增长而患上癫痫。BDNF的增加被证明扰乱了正常的结构组织 大鼠海马齿状回出现前颗粒细胞形态的改变 癫痫发作。我们假设BDNF慢性地驱动齿状体内的结构变化逐渐 扰乱门控功能，导致癫痫发作的出现；从这个意义上说，它的增加可能构成 一些动物模型上常见的致痫线。在目标1中，我们将记录这些进展 从青壮年到成年，大脑网络活动和伴随行为的变化 在TgBDNF模型中，使用脑电-视频联合监测出现惊厥发作。解剖学 技术将绘制大脑结构/电路图，显示这段时间内活动的变化。在《目标2》中，我们 将确定过量的BDNF本身是否足以产生成人产生的异常整合 GCS在TgBDNF小鼠惊厥发作的过程中。在目标3中，我们将测试是否适度、有条件 抑制齿状回TrkB的表达逆转癫痫的发生并恢复GCs的门控特性 TgBDNF模型。

Abstract Temporal lobe epilepsy (TLE) is the most prevalent form of partial epilepsy, often refractory to treatment, with limbic structures, including hippocampus, implicated in seizure generation. Once a seizure occurs, there is increased risk for seizure recurrence, and seizures themselves act to further establish aberrant networks. Even though this pattern of post-seizure progression is well studied in animal models of kindling in which an initial period of intense seizures is caused by chemical treatment or physiological induction, little is known about the mechanisms that produce a first seizure episode, especially when epilepsy emerges in the absence of genetic causes or injury. Kindling studies support a role for seizure-induced increases in hippocampal brain-derived neurotrophic factor (BDNF) signaling in the development of subsequent seizures, raising the possibility that normal BDNF functions may be co-opted by seizure activity to reshape synaptic organization. We can extrapolate that persistent disruptions in BDNF regulation per se may similarly reshape organization to favor formation of pro- epileptic circuitry. This application uses a transgenic mouse strain that over-expresses the BDNF in the forebrain under the calcium/calmodulin-dependent kinase II alpha promoter (TgBDNF) as a model to study slow and progressive remodeling of synaptic circuits that marks the transition from normal to epileptic brain without prior kindling. A subset of TgBDNF mice develops spontaneous seizures in response to tail lifting & cage agitation at mid-adulthood with increasing numbers of mice becoming epileptic with age. Increased BDNF is shown to disrupt the normal structural organization of the hippocampal dentate gyrus by modifying the morphology of granule cells (GCs) prior to emergence of seizures. We hypothesize that BDNF chronically drives structural changes in the dentate to gradually disrupt gating function, leading to seizure emergence; and in this sense, its increase may constitute a common epileptogenic thread across some animal models. In Aim 1 we will document the progression of changes in brain network activity and accompanying behaviors, from young adulthood until convulsive seizures emerge, using combined EEG-video surveillance in TgBDNF model. Anatomical techniques will map the brain structures/circuits that show altered activity over this period. In Aim 2 we will determine if excess BDNF alone is sufficient to produce aberrant integration of adult-generated GCs on route to convulsive seizures in TgBDNF mice. In Aim 3, we will test if modest, conditional inhibition of dentate TrkB expression reverses epileptogenesis and restores gating properties of GCs in the TgBDNF model.