title: Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1.
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.
authors.affiliation: 1] Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow, UK [2] Centre for Neuroscience (CeNsUS), University of Strathclyde, Glasgow, UK [3] Psychiatric Research Institute for Neuroscience in Glasgow (PsyRING), Universities of Glasgow and Strathclyde, Glasgow, UK.
authors.forename: N
authors.initials: N
authors.lastname: Dawson
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: M
authors.initials: M
authors.lastname: Kurihara
authors.affiliation: 1] Psychiatric Research Institute for Neuroscience in Glasgow (PsyRING), Universities of Glasgow and Strathclyde, Glasgow, UK [2] Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Thomson
authors.affiliation: 1] Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow, UK [2] Centre for Neuroscience (CeNsUS), University of Strathclyde, Glasgow, UK [3] Psychiatric Research Institute for Neuroscience in Glasgow (PsyRING), Universities of Glasgow and Strathclyde, Glasgow, UK.
authors.forename: C L
authors.initials: CL
authors.lastname: Winchester
authors.affiliation: 1] Centre for Neuroscience (CeNsUS), University of Strathclyde, Glasgow, UK [2] Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: A
authors.initials: A
authors.lastname: McVie
authors.affiliation: Pfizer Neuroscience Research Unit, Cambridge, MA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Hedde
authors.affiliation: 1] School of Physiology and Pharmacology, University of Bristol, Bristol, UK [2] University of Exeter Medical School, University of Exeter, Hatherly Laboratories, Exeter, UK.
authors.forename: A D
authors.initials: AD
authors.lastname: Randall
authors.affiliation: 1] School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK [2] Regenerative Medicine Institute, School of Medicine, National University of Ireland, Galway, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Shen
authors.affiliation: Pfizer Neuroscience Research Unit, Cambridge, MA, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Seymour
authors.affiliation: Pfizer Neuroscience Research Unit, Cambridge, MA, USA.
authors.forename: Z A
authors.initials: ZA
authors.lastname: Hughes
authors.affiliation: Pfizer Neuroscience Research Unit, Cambridge, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Dunlop
authors.affiliation: 1] School of Physiology and Pharmacology, University of Bristol, Bristol, UK [2] University of Exeter Medical School, University of Exeter, Hatherly Laboratories, Exeter, UK.
authors.forename: J T
authors.initials: JT
authors.lastname: Brown
authors.affiliation: Pfizer Neuroscience Research Unit, Cambridge, MA, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: 1] Psychiatric Research Institute for Neuroscience in Glasgow (PsyRING), Universities of Glasgow and Strathclyde, Glasgow, UK [2] Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: B J
authors.initials: BJ
authors.lastname: Morris
authors.affiliation: 1] Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow, UK [2] Centre for Neuroscience (CeNsUS), University of Strathclyde, Glasgow, UK [3] Psychiatric Research Institute for Neuroscience in Glasgow (PsyRING), Universities of Glasgow and Strathclyde, Glasgow, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Pratt
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D007649:Ketamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009434:Neural Pathways / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D013788:Thalamus / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D007649:Ketamine; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C498794:Disc1 protein, mouse; C121001:NR2B NMDA receptor