Understanding psychiatric risk from DLG2 haploinsufficiency CNVs through the phenotyping of a Dlg2+/- rat model

Abstract

Copy number variants at the 11q14.1 locus are associated with multiple psychiatric conditions (e.g. Kirov et al., 2012; Gao et al., 2018). The candidate gene within this CNV, which is either completely deleted or duplicated, is DLG2 (coding PSD-93). PSD-93, a synaptic scaffold protein, stabilises effectors in the postsynaptic density of excitatory synapses. If PSD-93 content is altered key synaptic processes may be disrupted. Phenotyping a rat model heterozygous for Dlg2 (+/-), which models the deletion CNV in patients, can help isolate endophenotypes with cross-disorder relevance. At the protein level Dlg2+/- rats show a decrease in PSD-93 without changes to PSD-95 or NR1 expression. Ex-vivo structural MRI scans were analysed for white matter abnormalities and differences in grey matter volume; however no genotype effects were seen. Behavioural phenotyping was conducted using assays relevant to symptom domains seen in 11q14.1 deletion syndromes including anxiety, social behaviour, PCP-hyperlocomotion, and sensorimotor gating. Memory and learning in a battery of object recognition tasks and water-maze reference memory were assessed as an index of cognitive ability. Hedonic responses to stimuli, appetitive conditioning, and motivation to work for reward were assessed to capture reward processing. Finally, a novel paradigm to assess the propensity towards hallucinations and delusions in rodents was conducted. Dlg2+/- rats performed as wild-types on almost all measured domains and tasks. In many cases this presents a departure from findings with Dlg2 homozygous (-/-) knockout mice who demonstrate increased anxiety and deficient social behaviour. With the caveats of drawing conclusions across species and experiments, this highlights the importance of using the most clinically valid (i.e. heterozygous) models when characterising the effects of CNVs. Dlg2+/- rats showed a potentiated and sustained locomotor response to the psychostimulant PCP, showing that although its effects are subtle, deleting one copy of Dlg2 in a rat model does result in a compromised system with a possible psychosis susceptibility