A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

Abstract

Background: DLG2, also known as postsynaptic density protein-93 (PSD-93) or chapsyn-110, is an excitatory postsynaptic scaffolding protein that interacts with synaptic surface receptors and signaling molecules. A recent study has demonstrated that mutations in the DLG2 promoter region are significantly associated with autism spectrum disorder (ASD). Although DLG2 is well known as a schizophrenia-susceptibility gene, the mechanisms that link DLG2 gene disruption with ASD-like behaviors remain unclear. Methods: Mice lacking exon 14 of the Dlg2 gene (Dlg2-/mice) were used to investigate whether Dlg2 deletion leads to ASD-like behavioral abnormalities. To this end, we performed a battery of behavioral tests assessing locomotion, anxiety, sociability, and repetitive behaviors. In situ hybridization was performed to determine expression levels of Dlg2 mRNA in different mouse brain regions during embryonic and postnatal brain development. We also measured excitatory and inhibitory synaptic currents to determine the impacts of Dlg2 deletion on synaptic transmission in the dorsolateral striatum. Results: Dlg2-/mice showed hypoactivity in a novel environment. They also exhibited decreased social approach, but normal social novelty recognition, compared with wild-type animals. In addition, Dlg2-/mice displayed strong self-grooming, both in home cages and novel environments. Dlg2 mRNA levels in the striatum were heightened until postnatal day 7 in mice, implying potential roles of DLG2 in the development of striatal connectivity. In addition, the frequency of excitatory, but not inhibitory, spontaneous postsynaptic currents in the Dlg2-/dorsolateral striatum was significantly reduced. Conclusion: These results suggest that homozygous Dlg2 deletion in mice leads to ASD-like behavioral phenotypes, including social deficits and increased repetitive behaviors, as well as reductions in excitatory synaptic input onto dorsolateral spiny projection neurons, implying that the dorsal striatum is one of the brain regions vulnerable to the developmental dysregulation of DLG2.

From Hyposociability to Hypersociability—The Effects of PSD-95 Deficiency on the Dysfunctional Development of Social Behavior

“…There was also increased PSD-93 protein expression in hippocampal synapse of PSD-95 +/− mice, whereas the changes in the mPFC and other regions were not examined (Winkler et al, 2018 ). Consistently, DLG2 (also known as PSD-93 or chapsyn-110) deficient in mice also led to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum (Yoo et al, 2020 ). These data further suggest that both PSD-95 and PSD-93 are involved in processing social stimuli and social behavior control, indicating their functional redundancy (Winkler et al, 2018 ).…”

Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity

“…Indeed, Dlg2-/-mice have been shown to have impaired performance in the object-location paired associates learning task(36). Homozygous Dlg2-/-mice also exhibit increased grooming behaviour (35) and altered social interaction but without consistent effects in negative valence tasks such as the open field test (35,37).…”

“…Uniquely to the MAGUK family, DLG2 is targeted to the axon initial segment where it regulates neuronal excitability via its interactions with potassium channels (25,31). At a functional level, homozygous Dlg2-/-knockout mice have altered glutamatergic synapse function (32)(33)(34)(35) and impaired long-term potentiation (LTP) in the hippocampus (33). These synaptic perturbations could underlie the common cognitive psychopathologies of the psychiatric disorders associated with DLG2.…”

Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer’s disease-associated genes: DTNB and DLG2

“…DLG2 has previously been associated with schizophrenia 23 and autism 24,25 . Along these lines, DLG2 deficiency in mice has been reported to lead to reduced sociability and increased repetitive behavior along with aberrant synaptic transmission in the dorsal striatum 26 .…”