Molecular Mechanism of Synapse Assembly and Function

突触连接的强度在决定内部的信息流方面起着关键作用。 神经回路，并建立电路如何可以修改，以响应不断变化的输入。一 突触强度的关键参数是神经递质从突触释放的概率。 突触前神经元神经递质释放依赖于局部钙内流触发 突触前末梢特化区域的分子引发突触囊泡融合 称为活跃区。我们和其他人已经发现，活性区的保守蛋白质 细胞基质调节释放概率的关键决定因素，包括释放的数量， 准备突触囊泡，钙通道群集，和空间耦合的囊泡和 渠道突触前释放特性甚至在突触的相邻AZ之间也有相当大的变化。 同样的神经元。然而，保守的AZ细胞基质的蛋白质如何在局部作用以产生一种 突触强度的多样性尚不清楚。新的观察，包括我们自己的 初步数据表明，AZ细胞基质蛋白在功能上差异部署， 不同的突触，这表明了实现功能多样性的灵活策略。在这里，我们建造 我们在理解突触功能的局部决定因素方面的进展，以阐明 活性区被组织以实现突触特异性神经递质释放特性 (Aim 1），突触在可塑性过程中如何重组（目标2），以及功能如何 异质性与可塑性相互作用，以支持电路功能对变化的输入做出响应 (Aim 3）。

The strength of synaptic connections plays a critical role in determining information flow within neural circuits and establishing how circuits can be modified in response to changing inputs. A key parameter of synaptic strength is the probability of neurotransmitter release from the presynaptic neuron. Neurotransmitter release depends on localized calcium influx triggering fusion of molecularly primed synaptic vesicles at specialized domains of presynaptic terminals called active zones. We and others have found that conserved proteins of the active zone cytomatrix regulate key determinants of release probability, including the number of release- ready synaptic vesicles, calcium channels clustering, and the spatial coupling of vesicles and channels. Presynaptic release properties vary considerably even between neighboring AZs of the same neuron. Yet, how proteins of the conserved AZ cytomatrix act locally to generate a diversity of synaptic strengths is not understood. Emerging observations, including our own preliminary data, indicate that AZ cytomatrix proteins are differentially deployed at functionally distinct synapses, suggesting a flexible strategy for achieving functional diversity. Here, we build on our advances in understanding local determinants of synaptic function to elucidate how active zones are organized to achieve synapse-specific neurotransmitter release properties (Aim 1), how synapses are reorganized during plasticity (Aim 2), and how functional heterogeneity interacts with plasticity to support circuit function in response to changing inputs (Aim 3).