👤 Simonas Griesius

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. Show less

Copy number variants indicating loss of function in the DLG2 gene have been associated with markedly increased risk for schizophrenia, autism spectrum disorder, and intellectual disability. DLG2 encodes the postsynaptic scaffolding protein DLG2 (PSD93) that interacts with NMDA receptors, potassium channels, and cytoskeletal regulators but the net impact of these interactions on synaptic plasticity, likely underpinning cognitive impairments associated with these conditions, remains unclear. Here, hippocampal CA1 neuronal excitability and synaptic function were investigated in a novel clinically relevant heterozygous Dlg2+/- rat model using ex vivo patch-clamp electrophysiology, pharmacology, and computational modelling. Dlg2+/- rats had reduced supra-linear dendritic integration of synaptic inputs resulting in impaired associative long-term potentiation. This impairment was not caused by a change in synaptic input since NMDA receptor-mediated synaptic currents were, conversely, increased and AMPA receptor-mediated currents were unaffected. Instead, the impairment in associative long-term potentiation resulted from an increase in potassium channel function leading to a decrease in input resistance, which reduced supra-linear dendritic integration. Enhancement of dendritic excitability by blockade of potassium channels or activation of muscarinic M1 receptors with selective allosteric agonist 77-LH-28-1 reduced the threshold for dendritic integration and 77-LH-28-1 rescued the associative long-term potentiation impairment in the Dlg2+/- rats. These findings demonstrate a biological phenotype that can be reversed by compound classes used clinically, such as muscarinic M1 receptor agonists, and is therefore a potential target for therapeutic intervention. Show less

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 Show less