Cellular and Circuit Mechanisms of Temporal Lobe Epilepsy

由颞叶引起的癫痫尤其具有破坏性，因为它既常见又普遍。 对抗惊厥药物的对症治疗有抵抗力。临床前和临床研究支持这一观点，即 癫痫持续状态发作后恢复有助于颞叶癫痫月的发展 或者几年后。对癫痫持续状态导致颞叶癫痫的机制的洞察可能 促进开发预防和/或改变疾病的疗法。我们最近发现了一种分子 癫痫持续状态导致颞叶癫痫的信号通路，即大脑激活- 衍生神经营养因子受体TrkB。这是一个重大的悬而未决的问题，需要在本申请中解决， 是如何将这种信号转化为构成颞叶基础的细胞和电路修改的 癫痫。癫痫持续状态引起TrkB激活的解剖部位提供了有价值的线索 对细胞的影响。主要部位是苔藓状纤维轴突的突触突触。 海马齿状颗粒细胞。这个应用程序的目标是测试我们统一的三个方面 假设：a)癫痫持续状态诱导苔藓纤维突触与两个CA3锥体可塑性 细胞和抑制性中间神经元；b)癫痫持续状态诱导这些可塑性需要TrkB；以及c) 苔藓纤维释放的递质是颞叶癫痫表现的基础。

Epilepsy arising from the temporal lobes is particularly devastating because it is both common and commonly resistant to symptomatic therapy with anticonvulsants. Preclinical and clinical studies support the idea that an episode of status epilepticus followed by recovery contributes to development of temporal lobe epilepsy months or years later. Insight into the mechanisms by which status epilepticus induces temporal lobe epilepsy may facilitate developing preventive and/or disease modifying therapies. We recently discovered a molecular signaling pathway by which status epilepticus induces temporal lobe epilepsy, namely activation of the brain- derived neurotrophic factor receptor, TrkB. A major unresolved question, to be addressed in this application, is how this signaling is transformed into the cellular and circuit modifications that underlie temporal lobe epilepsy. The anatomic locale at which status epilepticus induced activation of TrkB provides a valuable clue to the cellular consequences. The principal site was the synaptic boutons of the mossy fiber axons of hippocampal dentate granule cells. The objective of this application is to test three facets of our unifying hypothesis: a) that status epilepticus induces plasticities of mossy fiber synapses with both CA3 pyramidal cells and inhibitory interneurons; b) that status epilepticus induction of these plasticities requires TrkB; and c) that transmitter release from the mossy fibers underlies expression of temporal lobe epilepsy.