SRGAP2 limits experience-dependent structural synaptic plasticity in adult cortical circuits

In cortical circuits, synaptic plasticity involves either changes in the weight of pre-existing synapses, referred to as functional synaptic plasticity, or synapse formation and elimination, referred to as structural synaptic plasticity. Experience-dependent structural synaptic plasticity is prominent in juvenile cortical circuits during critical periods of development but drastically decreases in adult cortical circuits. The molecular mechanisms limiting experience-dependent structural synaptic plasticity in adult cortical circuits remain largely unknown. During development, the postsynaptic protein SRGAP2 limits the formation of both excitatory (E) and inhibitory (I) synapses in cortical pyramidal neurons (CPNs) and promotes their maturation. SRGAP2 expression is maintained throughout adulthood but its synaptic function in the adult cortex has not been explored. Using longitudinal 2-photon (2P) imaging of dendritic spine dynamics in layer 2/3 CPNs and found that this form of sensory deprivation induces a striking increase in structural synaptic plasticity favoring spine formation in adult constitutive SRGAP2+/- mice, in contrast to wild-type adult mice, where whisker trimming does not induce significant structural synaptic plasticity. Using conditional, cell-type specific, deletion of SRGAP2, we demonstrate that this experience-dependent structural synaptic plasticity requires both of SRGAP2 in expression L2/3 CPNs and in microglia. We previously demonstrated that the human-specific paralogs SRGAP2B/C inhibit all known functions of SRGAP2, phenocopying SRGAP2 haploinsufficiency, our results suggest that SRGAP2B/C might endow increased levels of experience-dependent structural synaptic plasticity to human pyramidal neurons in adult cortical circuits.