Electrical Synapses and Network Signaling

描述（由申请人提供）：从蓝斑释放的去甲肾上腺素有力地控制海马体的电活动，并与注意力、记忆过程的调节和癫痫样活动的预防有关。具体而言，海马中去甲肾上腺素的优先突触靶点是GABA能中间神经元，其表达差距连接蛋白Connexin 36，并组织成电耦合网络。缝隙连接通过同步放电和促进阈下突触后电位的传播来塑造GABA能网络的活性和整合。本项目的主要目的是确定海马GABA能网络中缝隙连接调节的分子机制。我们将测试的总体假设，去甲肾上腺素调节电耦合是由特定的第二信使和蛋白激酶介导的，并控制网络动态。尽管大量的研究调查去甲肾上腺素能控制神经元的内在特性，电突触的调制是一个几乎未开发的领域在哺乳动物皮层GABA能电路。然而，控制神经元间耦合的强度可能会影响海马整合和网络动力学，这是基本认知功能的基础。此外，阐明缝隙连接调节的新机制可能为癫痫的治疗提供新的策略。在方法上，我们将利用体外电生理学、解剖学和药理学的组合应用于野生型和连接蛋白36敲除动物。尽管神经元通过化学突触和电突触进行交流，但目前大多数脑部疾病的药物治疗都是基于调节化学突触传递的药物。本论文将研究基于电突触的神经元通讯机制及其调控。发现突触调节的新机制可以揭示治疗干预的其他靶点，这些靶点可以被目前正在开发和测试的新一代药物所利用。

DESCRIPTION (provided by applicant): Noradrenaline released from the locus coeruleus powerfully controls the electrical activity of the hippocampus and has been implicated in the regulation of attention, memory processes, and in the prevention of epileptiform activity. Specifically, the preferential synaptic targets of noradrenaline in the hippocampus are GABAergic interneurons, which express the gap junction protein Connexin 36, and are organized in electrically coupled networks. Gap junctions shape GABAergic network activity and integration by synchronizing firing and boosting the propagation of subthreshold postsynaptic potentials. The broad aim of this project is the identification of molecular mechanisms of gap junction modulation in GABAergic networks of the hippocampus. We will test the overarching hypothesis that noradrenergic regulation of electrical coupling is mediated by specific second messengers and protein kinases, and controls network dynamics. Despite the abundance of studies investigating noradrenergic control of neuronal intrinsic properties, modulation of electrical synapses is a virtually unexplored field in mammalian cortical GABAergic circuits. However, the control of the strength of interneuronal coupling could impact hippocampal integration and network dynamics that are at the basis of essential cognitive functions. In addition, unraveling new mechanisms of gap junction regulation could suggest new therapeutic strategies against epilepsy. Methodologically, we will take advantage of a combination of electrophysiology in vitro, anatomy, and pharmacology applied to wild type and Connexin 36-knock out animals. PUBLIC HEALTH RELEVANCE Although neurons communicate by using both chemical and electrical synapses, most of the current pharmacological therapy of brain disease is based on drugs modulating chemical synaptic transmission. The work proposed here will study mechanisms of neuronal communication based on electrical synapses, and their regulation. Discovering new mechanisms of synaptic modulation could reveal additional targets for therapeutic intervention that could be exploited by a new generation of drugs, which is currently under development and testing.