Functional analysis of Neuroligin-Neurexin interactions in synaptic transmission

描述(由申请人提供)：越来越多的证据表明，自闭症谱系障碍(ASD)是由异常突触形成引起的，突触是脑细胞相互交流的特殊连接。在我们的中枢神经系统中，神经元网络是通过兴奋性和抑制性突触建立的。动物模型和患者研究支持这一假说，即神经元兴奋和抑制平衡(E-I平衡)的失调是ASD的病理生理特征之一，尽管调节E-I平衡的分子机制在很大程度上尚不清楚。对于正常的突触形成，兴奋性和抑制性突触依赖于两个关键的细胞黏附分子家族之间的相互作用。第一类是神经连接素异构体(NL1、NL2、NL3和NL4)，它们特异性地定位于兴奋性和抑制性突触后部位，调节突触功能。而NRXN1、Nrxn2和NRXN3则定位于突触前终末，并与突触后NL亚型形成“跨突触”蛋白质复合体。重要的是，NL1、NL3、NL4和NRXN1的突变和/或缺失与自闭症相关。此外，模拟人类NL3自闭症突变的突变小鼠表现出异常的E-I平衡和异常的抑制性突触功能。因此，了解Nrxn-NL3相互作用在抑制性突触传递中的功能作用将对我们理解ASD的分子机制产生深远的影响。我们建议研究跨突触分子NL3在功能性抑制性突触形成方面的作用。我们将确定哪些特定的Nrxn亚型与NL3相互作用，以形成功能性抑制性突触。拟议的研究将阐明ASD相关的跨突触分子如何调节突触功能，并应为理解ASD的病理生理学创造路线图。

DESCRIPTION (provided by applicant): Mounting evidence indicates that autism spectrum disorders (ASDs) arise from abnormal synapse formation, the specialized junctions through which brain cells communicate with each other. In our central nervous systems, neuronal networks are established through excitatory and inhibitory synapses. Animal models and patient studies support the hypothesis that dysregulation of the balance of neuronal excitation and inhibition (E-I balance) is one of the pathophysiological hallmarks of ASDs, although the molecular mechanisms regulating E-I balance are largely unknown. For proper synapse formation, excitatory and inhibitory synapses rely on interactions between two key families of cell adhesion molecules. The first are neuroligin isoforms (NL1, NL2, NL3 and NL4) which, which localize specifically at excitatory and inhibitory postsynaptic sites, and regulate synaptic function. In contrast, neurexin isoforms (Nrxn1, Nrxn2 and Nrxn3) are localized at presynaptic terminals, and form "trans-synaptic" protein complexes with postsynaptic NL isoforms. Importantly, mutations and/or deletions of NL1, NL3, NL4 and Nrxn1 are associated with ASDs. Furthermore, mutant mice that mimic the human NL3 autism mutation exhibit abnormal E-I balance and abnormal inhibitory synaptic function. Therefore, understanding the functional roles of Nrxn-NL3 interactions on inhibitory synaptic transmission will have a profound impact on our understanding of the molecular mechanisms underlying ASDs. We propose to study trans-synaptic molecules, NL3, with respect to the formation of functional inhibitory synapses. We will identify which specific Nrxn isoforms interact with NL3 for functional inhibitory synapse formation. The proposed studies will shed light on how ASD-associated trans-synaptic molecules regulate synaptic function and should create the roadmap towards understanding the pathophysiology of ASDs.