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

Abstract

{delta}-catenin is expressed in excitatory synapses and functions as an anchor for the glutamatergic AMPA receptor (AMPAR) GluA2 subunit in the postsynaptic density. The glycine 34 to serine (G34S) mutation in the{delta} -catenin gene is found in autism spectrum disorder (ASD) patients and induces loss of {delta}-catenin functions at excitatory synapses, which is presumed to underlie ASD pathogenesis in humans. However, how the G34S mutation causes loss of {delta}-catenin functions to induce ASD remains unclear. Here, using neuroblastoma cells, we discover that the G34S mutation generates an additional phosphorylation site for glycogen synthase kinase 3{beta} (GSK3{beta}). This promotes {delta}-catenin degradation and causes the reduction of {delta}-catenin levels, which likely contributes to the loss of {delta}-catenin functions. Synaptic {delta}-catenin and GluA2 levels in the cortex are significantly decreased in mice harboring the {delta}-catenin G34S mutation. The G34S mutation increases glutamatergic activity in cortical excitatory neurons while it is decreased in inhibitory interneurons, indicating changes in cellular excitation and inhibition. {delta}-catenin G34S mutant mice also exhibit social dysfunction, a common feature of ASD. Most importantly, inhibition of GSK3{beta} activity reverses the G34S-induced loss of {delta}-catenin function effects in cells and mice. Finally, using {delta}-catenin knockout mice, we confirm that {delta}-catenin is required for GSK3{beta} inhibition-induced restoration of normal social behaviors in {delta}-catenin G34S mutant animals. Taken together, we reveal that the loss of {delta}-catenin functions arising from the ASD-associated G34S mutation induces social dysfunction via alterations in glutamatergic activity and that GSK3{beta} inhibition can reverse {delta}-catenin G34S-induced synaptic and behavioral deficits. Significance Statement{delta}-catenin is important for the localization and function of glutamatergic AMPA receptors at synapses in many brain regions. The glycine 34 to serine (G34S) mutation in the{delta} -catenin gene is found in autism patients and results in the loss of {delta}-catenin functions. {delta}-catenin expression is also closely linked to other autism-risk genes involved in synaptic structure and function, further implying that it is important for the autism pathophysiology. Importantly, social dysfunction is a key characteristic of autism. Nonetheless, the links between {delta}-catenin functions and social behaviors are largely unknown. The significance of the current research is thus predicated on filling this gap by discovering the molecular, cellular, and synaptic underpinnings of the role of {delta}-catenin in social behaviors.