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

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 +/À 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 +/À rats show a 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, and partially dissimilar to behavioural deficits previously reported in Dlg2 +/À mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks.

A mild impairment in reversal learning in a bowl‐digging substrate deterministic task but not other cognitive tests in the Dlg2+/− rat model of genetic risk for psychiatric disorder

“…Both spatial versions of the task appeared to be easier for animals of both genotypes, as greater numbers were able to complete the acquisition and reversal phases of both the deterministic and probabilistic versions of the task. These pieces of evidence could be interpreted as being indicative of intact hippocampal function in the Dlg2+/− model, despite altered hippocampal physiology previously reported in the same Dlg2+/− model 33 and increased phencyclidine‐induced locomotion 37 . In light of the consistent numerical difference and direction in win‐stay and lose‐shift probabilities in the substrate deterministic and probabilistic versions of the BRLT, it is possible there is a difference in the BRLT resolution strategy across genotype that spans both versions of the task.…”

“…These findings could be interpreted as suggestive of grossly intact perirhinal cortex‐hippocampus function, 56 , 67 , 68 despite altered NMDA receptor signalling and plasticity reported in this rat Dlg2+/− model. 33 , 37 Although food restriction did increase the motivation of rats to lever press for reward in the modified progressive ratio task here, there was no indication of a genotype‐specific effect, suggesting that motivation is preserved in the Dlg2+/− rats. Likewise, there was no difference across genotype in the novelty‐suppressed feeding test, which can be viewed as a measure of anxiety.…”

“…We have recently demonstrated in the heterozygous Dlg2+/− rat model enhanced NMDA receptor currents, reduced input resistance, reduced dendritic arborisation, impaired dendritic integration, and associative plasticity, 33 potentially suggesting impacts on hippocampal dependent learning and cognitive flexibility. Here, in addition to complementing the work done using full knockout models of Dlg2, we have expanded upon our recent molecular, 37 physiological, 33 and behavioural 37 characterisation of the Dlg2+/− heterozygous rat model. Dlg2+/− rats exhibited a mild impairment in reversal learning in one of the naturalistic bowl‐digging reversal learning task.…”

“…These pieces of evidence could be interpreted as being indicative of intact hippocampal function in the Dlg2+/− model, despite altered hippocampal physiology previously reported in the same Dlg2+/− model 33 and increased phencyclidine‐induced locomotion. 37 In light of the consistent numerical difference and direction in win‐stay and lose‐shift probabilities in the substrate deterministic and probabilistic versions of the BRLT, it is possible there is a difference in the BRLT resolution strategy across genotype that spans both versions of the task. The possibility that the order in which the different versions of the BRLT were performed in played a role in task outputs should also be acknowledged, as the 4 versions of the BRLT were done in series.…”

“…The results of the tasks not reported in this article can be found in Waldron et al 2022. 37 Approximately equal numbers of male and female rats were used in cohorts 3–4. Cohort 1 and 2 consisted of male rats only.…”