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

Abstract

δ-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 δ-catenin gene has been found in autism spectrum disorder (ASD) patients and results in loss of δ-catenin functions at excitatory synapses, which is presumed to underlie ASD pathogenesis in humans. However, how the G34S mutation causes loss of δ-catenin functions to induce ASD remains unclear. Here, using neuroblastoma cells, we identify that the G34S mutation increases glycogen synthase kinase 3β (GSK3β)-dependent δ-catenin degradation to reduce δ-catenin levels, which likely contributes to the loss of δ-catenin functions. Synaptic δ-catenin and GluA2 levels in the cortex are significantly decreased in mice harboring the δ-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. δ-catenin G34S mutant mice also exhibit social dysfunction, a common feature of ASD. Most importantly, pharmacological inhibition of GSK3β activity reverses the G34S-induced loss of δ-catenin function effects in cells and mice. Finally, using δ-catenin knockout mice, we confirm that δ-catenin is required for GSK3β inhibition-induced restoration of normal social behavior in δ-catenin G34S mutant animals. Taken together, we reveal that the loss of δ-catenin functions arising from the ASD-associated G34S mutation induces social dysfunction via alterations in glutamatergic activity and that GSK3β inhibition can reverse δ-catenin G34S-induced synaptic and behavioral deficits.

Prenatal exposure to valproic acid reduces synaptic δ-catenin levels and disrupts ultrasonic vocalization in neonates

“…The acute loss of δ-catenin in vitro also impairs activity-dependent formation of spines (Brigidi et al, 2014). Furthermore, recent studies, including our own, suggest that δ-catenin deficiency induced by δ-catenin KO, an ASD-associated δ-catenin missense mutation, or δ-catenin knockdown significantly alters cortical neurons’ synaptic activity (Assendorp et al, 2022; Mendez-Vazquez et al, 2023). As prenatal exposure to VPA significantly reduces brain δ-catenin levels ( Fig.…”

“…Therefore, after being separated from their nest, pups’ activation of AgRP neurons in the arcuate nucleus is regulated by thermal insulation and is linked to the emission of USVs (Zimmer et al, 2019). δ-catenin is known to regulate neuronal activity by controlling synaptic AMPAR expression (Assendorp et al, 2022; Farooq et al, 2016; Kosik et al, 2005; Mendez-Vazquez et al, 2023; Restituito et al, 2011; Silverman et al, 2007; Yuan & Arikkath, 2017; Yuan et al, 2015). Additionally, we reveal that prenatal exposure of VPA significantly reduce synaptic δ-catenin and AMPAR levels ( Fig.…”

“…The δ -catenin gene harbors many deleterious missense mutations, copy number variation, and de novo mutations that are strongly associated with severely affected ASD patients from multiple families (Turner et al, 2015; Wang et al, 2016). Studies, including our own, demonstrate that a loss of δ-catenin functions contributes to the ASD-linked cellular pathology and social dysfunction (Mendez-Vazquez et al, 2023; Turner et al, 2015). Therefore, these results suggest that VPA-induced ASD can be mediated by the loss of δ-catenin functions.…”

“…Postnatal day 0 (P0) male and female CD-1 pups were used to produce mouse cortical neuron cultures as shown previously (Mendez-Vazquez et al, 2023; Sathler et al, 2022; Sathler et al, 2021; Sztukowski et al, 2018). Cortices were isolated from P0 CD-1 mouse brain tissues and digested with 10 U/mL papain (Worthington Biochemical Corp., LK003176).…”

“…In addition to structural deficits, VPA exposure decreases synaptic strength, as measured by AMPAR-mediated excitatory postsynaptic current (EPSC) amplitude (Chanda et al, 2019). Research, including our own, reveals that δ-catenin deficiency increases the synaptic excitation and inhibition ratio and intrinsic excitability in young cortical pyramidal neurons (Assendorp et al, 2022; Mendez-Vazquez et al, 2023). Additionally, both short-term and long-term synaptic plasticity are significantly impaired in the hippocampus of δ-catenin knockout (KO) mice (Israely et al, 2004).…”