Selective behavioural impairments in mice heterozygous for the cross disorder psychiatric risk gene DLG2

Pass, Rachel ORCID: https://orcid.org/0000-0002-3652-0126, Haan, Niels, Humby, Trevor ORCID: https://orcid.org/0000-0002-1840-1799, Wilkinson, Lawrence S. ORCID: https://orcid.org/0000-0002-9337-6124, Hall, Jeremy ORCID: https://orcid.org/0000-0003-2737-9009 and Thomas, Kerrie L. ORCID: https://orcid.org/0000-0003-3355-9583 2022. Selective behavioural impairments in mice heterozygous for the cross disorder psychiatric risk gene DLG2. Genes, Brain and Behavior 21 (4) , e12799. 10.1111/gbb.12799

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Abstract

Mutations affecting DLG2 are emerging as a genetic risk factor associated with neurodevelopmental psychiatric disorders including schizophrenia, autism spectrum disorder, and bipolar disorder. Discs large homolog 2 (DLG2) is a member of the membrane-associated guanylate kinase protein superfamily of scaffold proteins, a component of the post-synaptic density in excitatory neurons and regulator of synaptic function and plasticity. It remains an important question whether and how haploinsuffiency of DLG2 contributes to impairments in basic behavioural and cognitive functions that may underlie symptomatic domains in patients that cross diagnostic boundaries. Using a heterozygous Dlg2 mouse model we examined the impact of reduced Dlg2 expression on functions commonly impaired in neurodevelopmental psychiatric disorders including motor co-ordination and learning, pre-pulse inhibition and habituation to novel stimuli. The heterozygous Dlg2 mice exhibited behavioural impairments in long-term motor learning and long-term habituation to a novel context, but not motor co-ordination, initial responses to a novel context, PPI of acoustic startle or anxiety. We additionally showed evidence for the reduced regulation of the synaptic plasticity-associated protein cFos in the motor cortex during motor learning. The sensitivity of selective behavioural and cognitive functions, particularly those dependent on synaptic plasticity, to reduced expression of DLG2 give further credence for DLG2 playing a critical role in specific brain functions but also a mechanistic understanding of symptom expression shared across psychiatric disorders.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Neuroscience and Mental Health Research Institute (NMHRI) Psychology Medicine Biosciences MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	This is an open access article under the terms of the Creative Commons Attribution License
Publisher:	Wiley Open Access
ISSN:	1601-1848
Funders:	Wellcome Trust
Date of First Compliant Deposit:	10 February 2022
Date of Acceptance:	19 January 2022
Last Modified:	22 Sep 2023 21:14
URI:	https://orca.cardiff.ac.uk/id/eprint/147386

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