Regulation of Inhibitory Activity at Hippocampal Slices by Synapsin II and Rab3a

描述（由申请人提供）：癫痫是一种复杂的、多因素的神经系统疾病，现在人们普遍认识到突触传递的改变往往是这种疾病的核心。这使得人们对突触蛋白在这种疾病中的作用越来越感兴趣。最好的例子是突触蛋白，突触蛋白，这个应用的主要焦点。在小鼠中，突触素I或突触素II蛋白的缺失导致强烈的癫痫表型，临床研究表明突触素缺乏也与人类特发性癫痫有关。兴奋性/抑制性失衡可能是导致过度兴奋性的原因之一。申请人最近的研究通过直接证明突触素II缺失对谷氨酸产生不同的影响来支持这一假设

DESCRIPTION (provided by applicant): Epilepsy is a complex and multifactorial neurological disorder, and now it is widely appreciated that changes in synaptic transmission often lie at the core of this disease. This has led to an increased interest in the role of synaptic proteins in thi disease. The best example of this are synaptic proteins synapsins, the main focus of this application. In mice, the deletion of synapsin I or synapsin II proteins results in a strong epilepic phenotype, and clinical studies demonstrated that synapsin deficiency is also associated with idiopathic epilepsy in humans. It was suggested that excitatory/inhibitory imbalance is one of the possible causes of the observed overexcitability. The applicant's recent study supports this hypothesis by directly demonstrating that synapsin II deletion differentially affects glutamatergic and GABAergic transmission at hippocampal slices and that epileptiform activity in SynII(-) slices is likely to result from impaired inhibition. Interestingly, deletion of the synapsin bindin partner Rab3a can suppress the epileptic phenotype observed in synapsin II deleted animals. This is obviously a potentially important observation that could help identify novel targets for th treatment of epilepsy. The experiments proposed in this application should help clarify the synaptic mechanisms that underlie the epileptogenic effects of synapsin II deletion as well as the physiological basis for the anti- epileptogenic effects of Rab3a deletion. The Specific Aim 1 proposes to investigate the role of synapsin II in the regulation of synchronous and asynchronous inhibitory transmission. Inhibitory asynchronous release following high-frequency discharges is thought to regulate epileptiform activity, and our preliminary data suggests that synapsin II deletion decreases the inhibitory asynchronous component in CA1 hippocampal interneurons. To elucidate the mechanism by which the deletion of synapsin II inhibits asynchronous release component, we will employ paired recordings of inhibitory transmission at hippocampal slices to rigorously examine synchronous and asynchronous quantal release at synapsin II deleted animals. The Specific Aim 2 proposes to understand how Rab3a deletion modifies the effect of Syn II deletion on synchronous and asynchronous inhibitory transmission. Since the deletion of Rab3a can neutralize synapsin-dependent epileptic seizures, we propose to investigate the asynchronous release component in the Rab3a(-) and in the SynII(-)/Rab3a(-) double knockout (DKO) neurons. Our preliminary data suggests that Rab3a deletion can restore the inhibitory asynchronous component reduced by the deletion of synapsin II. To understand by how Rab3a deletion can rescue the SynII(-) phenotype, we will investigate systematically synchronous and asynchronous release component at Rab3(-) and SynII(-)/Rabs3(-) DKO hippocampal slices and test whether the Rab3a incorporation into the SynII(-)/Rab3a(-) synapses can restore the SynII(-) phenotype.