The impact of spatio-temporal calcium dynamics within presynaptic active zones on synaptic delay at the frog neuromuscular junction

The spatio-temporal calcium dynamics within presynaptic neurotransmitter release sites (active zones, AZs) at the time of synaptic vesicle fusion is critical for neurotransmitter release. Specifically, the relative arrangement and density of voltage gated calcium channels (VGCCs) as well as the concentration of calcium buffering proteins can play a large role in the timing, magnitude and plasticity of release by shaping the AZ calcium profile. However, a high-resolution understanding of the role of AZ structure on the spatiotemporal calcium dynamics and how that may contribute to functional heterogeneity at an adult synapse is currently lacking. We demonstrate that synaptic delay varies considerably across, but not within, individual synapses at the frog neuromuscular junction (NMJ). To determine how elements of the AZ could contribute to this variability, we performed a parameter search using a spatially realistic diffusion-reaction based computational model of a frog NMJ active zone (Dittrich et al., 2013, Ma et al., 2015). We demonstrate using our model that synaptic delay is sensitive to significant alterations in the spatio-temporal calcium dynamics within an AZ at the time of release caused by manipulations to the density and organization of VGCCs or by the concentration of calcium buffering proteins. Further, our data provide a framework for understanding how AZ organization and structure is important for understanding presynaptic function and plasticity.

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