Electrical Synapses and Network Signaling

描述(申请人提供)：从蓝斑释放的去甲肾上腺素有力地控制着海马体的电活动，并与注意力、记忆过程的调节和癫痫样活动的预防有关。具体地说，去甲肾上腺素在海马区的优先突触靶点是GABA能中间神经元，它们表达间隙连接蛋白间隙连接蛋白36，并以电子耦合网络的形式组织。缝隙连接通过同步放电和促进阈值下突触后电位的传播来塑造GABA能网络的活动和整合。这个项目的主要目标是识别海马区GABA能网络中缝隙连接调制的分子机制。我们将测试最重要的假设，即去甲肾上腺素对电耦合的调节是由特定的第二信使和蛋白激酶介导的，并控制网络动力学。尽管有大量研究研究去甲肾上腺素对神经元内在特性的控制，但电突触的调制在哺乳动物皮质GABA能回路中几乎是一个未被探索的领域。然而，控制神经元间耦合的强度可能会影响作为基本认知功能基础的海马区整合和网络动力学。此外，解开缝隙连接调节的新机制可能会为癫痫提供新的治疗策略。在方法上，我们将利用体外电生理学、解剖学和药理学的结合，应用于野生型和连接蛋白36基因敲除的动物。公共卫生相关性虽然神经元通过化学和电突触进行交流，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。本文提出的工作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能会揭示新一代药物可能利用的治疗干预的额外靶点，该药物目前正在开发和测试中。

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.