Molecular Mechanism of Synapse Assembly and Function

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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).