Highlights d GluD1 mediates the formation and specification of inhibitory synapses in the cortex d GluD1 forms trans-synaptic interactions via Cbln4, a protein secreted by SST + INs d GluD1 elicits agonist-dependent postsynaptic signaling via ARHGEF12 and PPP1R12A d GluD1 is a maverick iGluR operating through non-ionotropic mechanisms

Human-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.

Pyramidal neurons (PNs) are covered by thousands of dendritic spines receiving excitatory synaptic inputs. The ultrastructure of dendritic spines shapes signal compartmentalization, but ultrastructural diversity is rarely taken into account in computational models of synaptic integration. Here, we developed a 3D correlative light–electron microscopy (3D-CLEM) approach allowing the analysis of specific populations of synapses in genetically defined neuronal types in intact brain circuits. We used it to reconstruct segments of basal dendrites of layer 2/3 PNs of adult mouse somatosensory cortex and quantify spine ultrastructural diversity. We found that 10% of spines were dually innervated and 38% of inhibitory synapses localized to spines. Using our morphometric data to constrain a model of synaptic signal compartmentalization, we assessed the impact of spinous versus dendritic shaft inhibition. Our results indicate that spinous inhibition is locally more efficient than shaft inhibition and that it can decouple voltage and calcium signaling, potentially impacting synaptic plasticity.

Pyramidal neurons are covered by thousands of dendritic spines receiving excitatory synaptic inputs. The ultrastructure of dendritic spines shapes signal compartmentalization but ultrastructural diversity is rarely taken into account in computational models of synaptic integration. Here, we developed a 3D correlative light-electron microscopy (3D-CLEM) approach allowing the analysis of specific populations of synapses in genetically defined neuronal types in intact brain circuits. We used it to reconstruct segments of basal dendrites of layer 2/3 pyramidal neurons of adult mouse somatosensory cortex and quantify spine ultrastructural diversity. We found that 10% of spines were dually-innervated and 38% of inhibitory synapses localize to spines. Using our morphometric data to constrain a model of synaptic signal compartmentalization, we assessed the impact of spinous versus dendritic shaft inhibition. Our results indicate that spinous inhibition is locally more efficient than shaft inhibition and that it can decouple voltage and calcium signaling, potentially impacting synaptic plasticity.