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

δ-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 δ-catenin has been implicated in many neurological disorders. Some of these genetic alterations exhibit a profound loss of δ-catenin functions in excitatory synapses. We have shown that δ-catenin deficiency induced by the homozygous δ-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, δ-catenin haploinsufficiency contributes to severe autism and learning disabilities in humans. However, previous studies have used only homozygous δ-catenin deficiency models. Therefore, it is important to examine the effects of δ-catenin haploinsufficiency on animals' behaviors and excitatory synapses. Here, we use heterozygous δ-catenin KO and G34S mice as a δ-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 δ-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 δ-catenin haploinsufficiency significantly affects the levels of synaptic δ-catenin and AMPARs. Our findings thus suggest that δ-catenin haploinsufficiency affects animals' behaviors via altering glutamatergic synaptic activity.