Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder

Genetic evidence links disruptions in the DLG2 gene to increased risk for schizophrenia, autism, and intellectual disability. To explore psychiatric traits associated with reduced DLG2 function, a rat model with one functional copy of the Dlg2 gene (Dlg2+/-) was tested for anxiety, sensorimotor gating, reward responses, social behavior, and movement after phencyclidine administration. The rats showed reduced PSD-93 mRNA and protein without compensation from related genes. They exhibited an exaggerated locomotor response to phencyclidine, a hallmark of psychosis models, but no deficits in other behaviors. These findings suggest that DLG2 haploinsufficiency produces subtle, psychosis-related effects, unlike the more severe impairments seen in models with complete gene loss.

Study at a glance

Abstract

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2+/- rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2+/- rats show potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, providing a contrast to the gross deficits in Dlg2 homozygous models (Winkler, et al., 2018; Yoo et al., 2020a) which do not so specifically model the single chromosome DLG2 deletion in carriers of risk-associated copy number variants.