δ-catenin haploinsufficiency is sufficient to alter behaviors and glutamatergic synapses in mice

Abstract

{delta}-catenin (also known as CTNND2) functions as an anchor for the glutamatergic AMPA receptor (AMPARs) to regulate synaptic activity in excitatory synapses. Alteration in the gene coding {delta}-catenin has been implicated in many neurological disorders. Some of these genetic alterations exhibit a profound loss of {delta}-catenin functions in excitatory synapses. We have shown that {delta}-catenin deficiency induced by the homozygous {delta}-catenin knockout (KO) and autism-associated missense glycine 34 to serine (G34S) mutation significantly alters AMPAR-mediated synaptic activity in cortical neurons and disrupts social behavior in mice. Importantly, many genetic disorders are caused by haploinsufficiency. Indeed, {delta}-catenin haploinsufficiency contributes to severe autism and learning disabilities in humans. However, previous studies have used only homozygous {delta}-catenin deficiency models. Therefore, it is important to examine the effects of {delta}-catenin haploinsufficiency on animals behaviors and excitatory synapses. Here, we use heterozygous {delta}-catenin KO and G34S mice as a {delta}-catenin haploinsufficiency model to examine this idea. Multiple behavioral assays, a social behavior test, contextual fear conditioning, and an open field test, reveal that both {delta}-catenin KO and G34S haploinsufficiency significantly disrupt animals social behavior and fear learning and memory. Interestingly, only KO haploinsufficiency mice show anxiety-like behavior. A biochemical assay using brain extracts demonstrates that {delta}-catenin haploinsufficiency significantly affects the levels of synaptic {delta}-catenin and AMPARs. Our findings thus suggest that {delta}-catenin haploinsufficiency affects animals behaviors via altering glutamatergic synaptic activity.