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Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus

Citation

Sinclair, D and Cesare, J and McMullen, M and Carlson, GC and Hahn, CG and Borgmann-Winter, KE, Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus, Journal of Neurodevelopmental Disorders, 8 Article 14. ISSN 1866-1947 (2016) [Refereed Article]


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Copyright Statement

Copyright 2016 Sinclair et al. Licensed under Creative Commons CC0 1.0 Universal (CC0 1.0)Public Domain Dedication https://creativecommons.org/publicdomain/zero/1.0/

DOI: doi:10.1186/s11689-016-9148-7

Abstract

Background:Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia differentially impact males and females and are highly heritable. The ways in which sex and genetic vulnerability influence the pathogenesis of these disorders are not clearly understood. The N-methyl-D-aspartate (NMDA) receptor pathway has been implicated in schizophrenia and autism spectrum disorders and changes dramatically across postnatal development at the level of the GluN2B-GluN2A subunit "switch" (a shift from reliance on GluN2B-containing receptors to reliance on GluN2A-containing receptors). We investigated whether sex and genetic vulnerability (specifically, null mutation of DTNBP1 [dysbindin; a possible susceptibility gene for schizophrenia]) influence the developmental GluN2B-GluN2A switch.

Methods: Subcellular fractionation to enrich for postsynaptic density (PSD), together with Western blotting and kinase assay, were used to investigate the GluN2B-GluN2A switch in the cortex and hippocampus of male and female DTNBP1 null mutant mice and their wild-type littermates. Main effects of sex and DTNBP1 genotype, and interactions with age, were assessed using factorial ANOVA.

Results: Sex differences in the GluN2B-GluN2A switch emerged across development at the frontal cortical synapse, in parameters related to GluN2B. Males across genotypes displayed higher GluN2B:GluN2A and GluN2B:GluN1 ratios (p < 0.05 and p < 0.01, respectively), higher GluN2B phosphorylation at Y1472 (p < 0.01), and greater abundance of PLCγ (p < 0.01) and Fyn (p = 0.055) relative to females. In contrast, effects of DTNBP1 were evident exclusively in the hippocampus. The developmental trajectory of GluN2B was disrupted in DTNBP1 null mice (genotype age interaction p < 0.05), which also displayed an increased synaptic GluN2A:GluN1 ratio (p < 0.05) and decreased PLCγ (p < 0.05) and Fyn (only in females; p < 0.0005) compared to wild-types.

Conclusions: Sex and DTNBP1 mutation influence the GluN2B-GluN2A switch at the synapse in a brain-regionspecific fashion involving pY1472-GluN2B, Fyn, and PLCγ. This highlights the possible mechanisms through which risk factors may mediate their effects on vulnerability to disorders of NMDA receptor dysfunction.

Item Details

Item Type:Refereed Article
Keywords:sex, DTNBP1, dysbindin, NMDA receptor, brain
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Cellular Nervous System
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
UTAS Author:Sinclair, D (Dr Duncan Sinclair)
ID Code:130627
Year Published:2016
Web of Science® Times Cited:4
Deposited By:Wicking Dementia Research and Education Centre
Deposited On:2019-02-06
Last Modified:2019-04-08
Downloads:3 View Download Statistics

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