Synaptic and cellular changes lead to aberrant hippocampal function in the DLG2+/- (PSD93+/-) rat

Abstract

DLG2 gene variants are linked to psychiatric disorders such as schizophrenia and autism spectrum. The DLG2 gene encodes the scaffolding protein DLG2 (PSD93) that interacts with glutamatergic receptors, potassium channels, and cytoskeletal regulators at the postsynaptic density. However, the impacts of these interactions and of reduced DLG2 expression on neuronal function are unknown.
Here, a heterozygous (het) DLG2+/- rat model was investigated using patch-clamp electrophysiology, pharmacology, computational modelling, and behaviour. Despite having increased NMDA receptor-mediated synaptic current, DLG2+/- hets had impaired dendritic integration and associative long-term potentiation (aLTP). DLG2+/- neurons exhibited reduced dendritic arborisation but had reduced input resistance. Computational modelling confirmed the incongruence between reduced dendric arborisation and reduced input resistance, suggesting that potassium conductance was increased in DLG2+/- hets. Further computational modelling showed that the presence of A-type potassium channels reduced input resistance and abolished supralinear dendritic integration in a wild type model. Pharmacological blockade of potassium channels increased input resistance and reduced the threshold for dendritic integration in DLG2+/- hets. Muscarinic M1 receptor agonism increased input resistance and reduced the threshold for dendritic integration in the DLG2+/- hets. Muscarinic M1 receptor agonism also rescued aLTP in the DLG2+/- hets. DLG2+/- hets had impaired reversal learning, presenting a phenotype for future behavioural rescue.
In parallel, work on antidepressant drug (AD) characterisation was performed. Conventional delayed-onset ADs used to treat symptoms of major depressive disorder (MDD) have limited efficacy for the motivational impairments associated with the disorder. Rapid-acting ADs, ketamine and scopolamine, have been put forward as efficacious treatments for MDD but their effects on motivation are unknown. Here, the effects of delayed-onset and rapid-acting ADs on motivation were compared using the effort for reward task (EfRT) on wildtype female lister hooded rats. Effort-related choice behaviour in the EfRT was sensitive to dopaminergic manipulations and pre-feeding. Both conventional and rapid-acting ADs attenuated effort-related choice behaviour with no specific effects, with no evidence for rapid-acting AD-specific effects on effort-related choice behaviour.

Date of Award	2 Dec 2021
Original language	English
Awarding Institution	University of Bristol
Supervisor	Emma S J Robinson (Supervisor) & Jack R Mellor (Supervisor)