CTNND2 moderates neuronal excitation and links human evolution to prolonged synaptic development in the neocortex

Abstract

ABSTRACTHuman-specific genes are potential drivers of brain evolution. Among them, SRGAP2C contributes to distinct features by extending the period of synaptic maturation and increasing cortical connectivity. Here we examined SRGAP2 protein-interaction network in developing synapses and identified catenin delta-2 (CTNND2) as a binding partner of human-specific SRGAP2C. CTNND2 is a cadherin-binding protein implicated in intellectual disability in the Cri-du-Chat syndrome, severe autism and epilepsy. Using sparse manipulations in upper layer cortical pyramidal neurons, we demonstrate that CTNND2 is an activity-limiting protein that coordinates synaptic excitation and inhibition and controls intrinsic excitability in juvenile mice. Later in adults, CTNND2 is required for long-term maintenance of dendritic spines. CTNND2 enrichment at excitatory synapses is enhanced by human-specific SRGAP2C. Thus, while loss of CTNND2 function accelerates synaptic development, causes overexcitation and homeostatic failure, its upregulation by SRGAP2C may contribute to synaptic neoteny in humans and protect against precocious synapse loss during aging.