Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1

Dawson, N. et al. (2015) Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1. Translational Psychiatry, 5(5), e569. (doi:10.1038/tp.2015.60) (PMID:25989143)

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Abstract

Considerable evidence implicates DISC1 as a susceptibility gene for multiple psychiatric diseases. DISC1 has been intensively studied at the molecular, cellular and behavioral level, but its role in regulating brain connectivity and brain network function remains unknown. Here, we utilize a set of complementary approaches to assess the functional brain network abnormalities present in mice expressing a truncated Disc1 gene (Disc1tr Hemi mice). Disc1tr Hemi mice exhibited hypometabolism in the prefrontal cortex (PFC) and reticular thalamus along with a reorganization of functional brain network connectivity that included compromised hippocampal–PFC connectivity. Altered hippocampal–PFC connectivity in Disc1tr Hemi mice was confirmed by electrophysiological analysis, with Disc1tr Hemi mice showing a reduced probability of presynaptic neurotransmitter release in the monosynaptic glutamatergic hippocampal CA1–PFC projection. Glutamate system dysfunction in Disc1tr Hemi mice was further supported by the attenuated cerebral metabolic response to the NMDA receptor (NMDAR) antagonist ketamine and decreased hippocampal expression of NMDAR subunits 2A and 2B in these animals. These data show that the Disc1 truncation in Disc1tr Hemi mice induces a range of translationally relevant endophenotypes underpinned by glutamate system dysfunction and altered brain connectivity.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Thomson, Dr David and Brandon, Dr Nicholas and Winchester, Dr Catherine and Morris, Professor Brian
Authors: Dawson, N., Kurihara, M., Thomson, D.M., Winchester, C.L., McVie, A., Hedde, J.R., Randall, A.D., Shen, S., Seymour, P.A., Hughes, Z.A., Dunlop, J., Brown, J.T., Brandon, N.J., Morris, B.J., and Pratt, J.A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Translational Psychiatry
Publisher:Nature Publishing Group
ISSN:2158-3188
ISSN (Online):2158-3188
Copyright Holders:Copyright © 2015 Macmillan Publishers Limited
First Published:First published in Translational Psychiatry 5(5):e569
Publisher Policy:Reproduced under a Creative Commons License

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