Neocortical High Probability Release Sites are Formed by Distinct Ca ²⁺ Channel to Release Sensor Topographies During Development

Abstract

Coupling distances between Ca²⁺ channels and release sensors regulate the vesicular release probability (p_r). Tight coupling is thought to provide a framework for high pr and loose coupling for high plasticity at low p_r. At synapses investigated during development, coupling distances decreased, thereby, increasing p_r and transfer fidelity. We found neocortical high-fidelity synapses to deviate from these rules. Paired recordings from pyramidal neurons with ‘slow’ and ‘fast’ Ca²⁺ chelators combined with experimentally constrained simulations suggest that coupling tightened significantly during development. However, fluctuation analysis revealed that neither p_r (~0.63) nor the number of release sites (~8) changed concomitantly, although amplitude and time-course of presynaptic Ca²⁺ transients were not different between age groups. These results are explained by high-p_r release sites with Ca²⁺ microdomains in young and nanodomains in mature synapses. Thus, developmental reorganization of the active zone left pr unaffected at a neocortical synapse, emphasizing developmental and functional synaptic diversity.

Keywords: Pyramidal neurons, neocortex, quantal parameters, Ca2+ imaging, Ca2+ channel subtypes, EGTA, BAPTA, numerical simulations, coupling, microdomain, nanodomain