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

Abstract

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.

The autism-associated loss of δ-catenin functions disrupts social behaviors

“…Moreover, postsynaptic glutamatergic activity in cortical excitatory or inhibitory neurons controls social behavior via the regulation of neuronal E/I within the cortical neural network (13, 19). Consistently, a recent study shows that δ-catenin deficiency increases the E/I ratio and intrinsic excitability in young cortical excitatory cells (31). Given that GluA2 levels are significantly reduced in the δ-catenin G34S cortex ( Fig.…”

“…Finally, we show that δ-catenin is required for lithium-induced restoration of normal social behavior in δ-catenin G34S mice. As the expression of δ-catenin is highly correlated with other ASD-risk genes that are involved in synaptic structure and function (31,(36)(37)(38), our findings can help us to better understand ASD synaptopathy.…”

“…The copyright holder for this preprint this version posted January 13, 2023. ; https://doi.org/10.1101/2023.01.12.523372 doi: bioRxiv preprint function, such as GluA2, cadherins, GRIP, and synaptic Ras GTPase activating protein 1 (SYNGAP1), further implying that it is important for synaptic pathophysiology and social dysfunctions in ASD (31,(36)(37)(38).…”

“…Importantly, some δ-catenin ASD mutations are unable to reverse the δ-catenin deficiency-induced reduction of excitatory synapse density in cultured mouse neurons, suggesting that these mutations cause a loss of δ-catenin functions (24). A recent study reveals that δ-catenin knockdown increases the synaptic excitation and inhibition ratio and intrinsic excitability in young cortical pyramidal cells (31). Thus, this suggests that δ-catenin deficiency induces ASD-associated social deficits via impairment of glutamatergic synapses.…”

“…Thus, this suggests that δ-catenin deficiency induces ASD-associated social deficits via impairment of glutamatergic synapses. Moreover, δ-catenin expression is closely linked to other ASD-risk genes involved in synaptic structure and function, such as GluA2, cadherins, GRIP, and synaptic Ras GTPase activating protein 1 (SYNGAP1), further implying that it is important for synaptic pathophysiology and social dysfunctions in ASD (31, 36–38). Nonetheless, the molecular and cellular links between δ-catenin functions, synaptic activity, and social behaviors are largely unknown.…”