Effects of TrkB Activation on Abnormalities in Neocortical FS interneuron

项目摘要 小白蛋白(PV)和生长抑素(SOM)中间神经元异常在许多 神经紊乱，包括癫痫。改善有缺陷的中间神经元功能的疗法不是 可用。中间神经元的结构发育和维持依赖于提供的营养支持 通过脑源性神经营养因子激活TrkB受体(TrkB-Rs)。在底切(UC)模型中 癫痫样新皮质损伤，选择性小分子部分激动剂对TrkB-Rs的慢性激活 (LM22A-4，下文“LM”)对逆转抑制性脑结构和功能异常具有长期作用。 PV中间神经元终末促进GABA释放并提高致痫阈值 活动和癫痫发作。家长资助的主要目标是确定这些影响是否适用于 在其他模型中治疗或预防癫痫发作的不同原因。我们的目标是 确定TrkB-Rs部分激动剂是否通过增加神经释放GABA来进行慢性治疗 中间神经元的终末，或诱导新的抑制性突触形成，将加强皮质的抑制 网络和抑制癫痫样放电。家长资助的具体目的包括：i)测试 假设用LM激活TrkB-R将逆转或防止FS的结构异常 UC皮质中间神经元；II)TrkB-Rs激活对GABA能神经元功能特性的影响 第V层抑制；iii)测试LM对UC动物大脑皮层网络活动的影响。建议的实验 包括a)免疫细胞化学和共聚焦成像，以评估突触前终末的变化 B)PV抑制性突触传递基本特性的电生理学分析 以检测TrkB激活对单个IPSCs的影响。 释放概率和传输失败。对于这项补充拨款，我们将研究焦点地位的影响 癫痫对大脑皮层网络GABA能中间神经元数量、形态和生理的影响 并测试小分子部分激动剂PTXBD4-3激活TrkB-Rs的可能缓解效果 (BD)。这些成果将补充和扩大父母赠款的目标1和目标2。这些措施的结果 实验将提供从神经元间异常到 癫痫的发展和加强营养预防癫痫发生的潜在途径 中间神经元的支持。考虑到FSE的频率和不良后果，结果可能会 潜在的翻译重要性。

Project Summary Abnormalities in parvalbumin (PV) and somatostatin (SOM) interneurons are reported in a number of neurological disorders, including epilepsy. Therapy that improves function of defective interneurons is not available. Structural development and maintenance of interneurons is dependent on trophic support provided by brain derived neurotrophic factor activation of TrkB receptors (TrkB-Rs). In the undercut (UC) model of epileptogenic neocortical injury, chronic activation of TrkB-Rs with a selective small molecule partial agonist (LM22A-4, “LM” below) has long-term effects to reverse structural and functional abnormalities in inhibitory terminals of PV interneurons, enhance GABA release and increase the threshold for evoking epileptiform activity and seizures. The parent grant main goal is to determine whether these effects will be applicable to treatment or prevention of epilepsy in other models with different causes for seizures. The objective is to determine whether chronic treatment with a TrkB-Rs partial agonist, by increasing GABA release from nerve terminals of interneurons, or inducing new inhibitory synapse formation, will enhance inhibition in cortical networks and suppress epileptiform discharges. The specific aims of the parent grant include to: i) test the hypothesis that activation of TrkB-Rs with LM will reverse or prevent structural abnormalities in FS interneurons of UC cortex; ii) Examine effects of TrkB-Rs activation on functional properties of GABAergic inhibition in layer V; iii) Test the effects of LM on cortical network activity in UC animals. Proposed experiments include a) immunocytochemistry and confocal imaging to assess alterations in presynaptic terminals of interneurons; b) electrophysiological analysis of basic properties of inhibitory synaptic transmission from PV interneurons to pyramidal neurons of in vitro slices to detect effects of TrkB activation on unitary IPSCs, release probability and transmission failures. For this supplement grant we will study the effects of focal status epilepticus (FSE) on numbers, morphology and physiology of GABAergic interneurons in the cortical network and test possible mitigating effects of activation of TrkB-Rs with a small molecule partial agonist, PTXBD4-3 (BD). These results will complement and extend Aims 1, and 2 of the parent grant. Results of these experiments will provide information about mechanisms leading from interneuronal abnormalities to development of epilepsy and a potential approach to prophylaxis of epileptogenesis by enhancing trophic support of interneurons. Considering the frequency and untoward consequences of FSE, results may have potential translational importance.