Molecular mechanism of synapse assembly and function

突触连接的强度在决定脑内信息流方面起着关键作用。 神经电路和建立如何根据变化的输入来修改电路。一个 突触强度的关键参数是神经递质从脑内释放的可能性 突触前神经元。神经递质的释放依赖于局部钙内流触发 突触前终末特化区域内分子启动突触小泡的融合 称为活动区。我们和其他人发现活动区的保守蛋白质 Cytomatrix调节释放概率的关键决定因素，包括释放的数量- 准备好的突触小泡，钙通道聚集，以及小泡和钙通道的空间耦合 频道。即使在相邻的AZ之间，突触前释放特性也有很大的差异 同样的神经元。然而，保守的AZ Cytomatrix的蛋白质是如何在局部作用产生 突触强度的多样性尚不清楚。新出现的观测，包括我们自己 初步数据表明，AZ Cytomatrix蛋白在功能上存在差异 截然不同的突触，暗示了实现功能多样性的灵活策略。在这里，我们建造 关于我们在理解突触功能的局部决定因素方面的进展 活动区被组织起来以实现突触特定的神经递质释放特性 (目标1)，突触在可塑性过程中如何重组(目标2)，以及功能如何 异构性与可塑性相互作用，以支持电路功能以响应不断变化的输入 (目标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).