Mechanisms of Silent Synapse Maturation for Excitatory Network Refinement

Abstract Silent synapses are instrumental in experience-dependent cortical network reorganization. This process is particularly prevalent during developmental critical periods when silent synapses are abundant. Genesis, loss, and maturation of these silent synapses alters the synaptic connection pattern to establish the fundamental processing architectures of excitatory neural networks during critical periods. Whether silent synapses mature or are lost is a critical decision point to determine the fate of synaptic connections between neurons. Thus, the delicate balance of the pace of silent synapse maturation and their loss determines the outcome of the refinement process during critical periods. However, the molecular underpinnings regulating the pace of silent synapse maturation and how changes in pace impact local neural circuits and sensory perception remains elusive. Our previous studies report that the pace is controlled by the opposing but cooperative function of two postsynaptic signaling scaffolds, PSD-93 and -95, that inhibits and promotes silent synapse maturation, respectively. Using unbiased quantitative phosphoproteomic approaches, we identified signaling pathways affected by PSD-93 and -95 that govern the maturation. The proposed experiments employ genetic manipulations using viral vectors and transgenic mouse models, combined with electrophysiological analysis, quantitative proteomic analyses, and confocal imaging to focus on a fundamentally new concept of silent-synapse based mechanism driving experience-dependent cortical development. Results will reveal a so far unknown signaling mechanism in regulating the pace of silent synapse maturation. Expected results will advance our understanding of the molecular mechanisms of neural network refinement, and their impact on local circuits and visual perception, exemplified in the primary visual cortex, but relevant to cortical networks in general.