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

Abstract

Variations in the Dlg2 gene have been linked to increased risk for psychiatric disorders, including schizophrenia, autism spectrum disorders, intellectual disability, bipolar disorder, attention deficit hyperactivity disorder, and pubertal disorders. Recent studies have reported disrupted brain circuit function and behaviour in models of Dlg2 knockout and haploinsufficiency. Specifically, deficits in hippocampal synaptic plasticity were found in heterozygous Dlg2+/− rats suggesting impacts on hippocampal dependent learning and cognitive flexibility. Here, we tested these predicted effects with a behavioural characterisation of the heterozygous Dlg2+/− rat model. Dlg2+/− rats exhibited a specific, mild impairment in reversal learning in a substrate deterministic bowl‐digging reversal learning task. The performance of Dlg2+/− rats in other bowl digging task, visual discrimination and reversal, novel object preference, novel location preference, spontaneous alternation, modified progressive ratio, and novelty‐suppressed feeding test were not impaired. These findings suggest that despite altered brain circuit function, behaviour across different domains is relatively intact in Dlg2+/− rats, with the deficits being specific to only one test of cognitive flexibility. The specific behavioural phenotype seen in this Dlg2+/− model may capture features of the clinical presentation associated with variation in the Dlg2 gene.

Impaired reversal learning in the Dlg2+/− rat model of genetic risk for psychiatric disorder: Important questions regarding the neuro‐behavioral mechanisms of reversal learning

“…In summary, Griesius et al 1 show that disruption of the Dlg2 gene can cause a relatively specific reversal learning impairment. Whether hippocampal synaptic dysfunction, which is prominent in the Dlg2+/− rats, contributes to reversal learning impairment remains to be determined.…”

“…A main focus of neuroscience research on reversal learning has been on fronto‐striatal mechanisms, especially involving orbitofrontal cortex. 2 , 4 However, Griesius et al 1 highlight that Dlg2+/− rats show reduced hippocampal synaptic integration and plasticity 5 and propose this may contribute to reversal learning impairments (although Dlg2+/− rats probably have other neuronal dysfunction, outside the hippocampus, that may explain the impairments). Indeed, human 6 , 7 and animal model 8 , 9 studies have implicated the hippocampus in reversal learning (for a discussion of how hippocampal contributions to reversal learning may relate to theories of hippocampal function, see Reference 8 ).…”

“…Indeed, human 6 , 7 and animal model 8 , 9 studies have implicated the hippocampus in reversal learning (for a discussion of how hippocampal contributions to reversal learning may relate to theories of hippocampal function, see Reference 8 ). Overall, Griesius et al 1 draw attention to the possibility that reversal learning may depend on brain substrates outside fronto‐striatal circuits, including hippocampal mechanisms, although this requires confirmation by future studies.…”

“…Second, why is one reversal task impaired, but not others? A strength of the study by Griesius et al 1 is the use of different reversal tasks, with different procedural demands. Interestingly, Dlg2+/− rats only showed reversal impairments on one of these tasks.…”

“…Dlg2+/-, reversal, rat, psychiatric disorders, hippocampus, schizophrenia, behavior, bowl digging, touch screen, animal model Griesius et al 1 report that heterozygous Dlg2+/À rats showed a specific reversal learning impairment on a deterministic substrate-specific bowl-digging task, whereas reversal on other bowl-digging tasks (probabilistic substrate-specific and both deterministic and probabilistic spatial) and a touch-screen visual-discrimination task was unaffected (alongside normal behavior on a range of other tests). The Dlg2 gene encodes the synaptic protein PSD3, and Dlg2 disruption has been associated with psychiatric disorders, including schizophrenia.…”