Formation of Neuronal Cholinergic Synapses

描述(由申请人提供)：精确的突触连接对于神经系统的正常功能是必不可少的。然而，令人惊讶的是，我们对体内神经元-神经元突触形成的调控机制知之甚少。本应用拟以小鼠颈上神经节(SCG)内简单易得的外周突触为模型系统，研究神经元-神经元突触的形成。这项拟议的研究的重点是确定调节神经元胆碱能突触的突触后装置组装的关键分子机制。神经元胆碱能系统在外周和中枢神经系统中都扮演着重要的角色。胆碱能功能的改变与几种神经疾病有关，包括阿尔茨海默病、S病和精神分裂症。目前，神经元胆碱能突触的形成、成熟和稳定的调控机制还完全不清楚。在这里，我们建议使用分子和遗传学的方法来阐明调控神经元胆碱能突触的突触后复合体组装的机制。第一个目的是确定神经元胆碱能突触的突触后信号复合体的分子组成，并了解突触后信号复合体是如何组装的。第二个目的是确定靶向/锚定神经元烟碱型乙酰胆碱受体到突触的分子机制。最后，我们将使用突变小鼠来测试我们已经在SCG突触中发现的一个突触后信号复合体蛋白的体内功能，并评估突触后信号复合体在神经元胆碱能突触的形成、成熟和稳定中的重要性。这些研究将促进我们对神经系统中精确的突触连接是如何建立和调节的理解。

DESCRIPTION (provided by applicant): Precise synaptic connectivity is essential for the proper function of the nervous system. Surprisingly, however, we know very little about mechanisms that regulate the formation of neuron-neuron synapses in vivo. This application proposes to use the simple and accessible peripheral synapse in the mouse superior cervical ganglion (SCG) as a model system to study the formation of neuron-neuron synapses. The focus of this proposed research is to determine key molecular mechanisms that regulate the assembly of the postsynaptic apparatus at neuronal cholinergic synapses. Neuronal cholinergic systems play critical roles in both the peripheral and central nervous systems. Alterations in cholinergic function have been implicated in several neurological disorders, including Alzheimer' s disease and schizophrenia. Currently, mechanisms regulating the formation, maturation and stability of neuronal cholinergic synapses are completely unknown. Here, we propose to use molecular and genetic approaches to elucidate the mechanisms that regulate the assembly of the postsynaptic complex at neuronal cholinergic synapses. The first aim is to identify the molecular components of the postsynaptic signaling complex at neuronal cholinergic synapses and to understand how the postsynaptic signaling complex is assembled. The second aim is to determine the molecular mechanisms that target/anchor neuronal nicotinic acetylcholine receptors to synapses. Finally, we will use mutant mice to test the in vivo function of one postsynaptic signaling complex protein we already identified at the SCG synapse and assess the importance of the postsynaptic signaling complex in the formation, maturation and stability of neuronal cholinergic synapses. These studies will advance our understanding of how the precise synaptic connectivity in the nervous system is established and regulated.