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

N Dawson, M Kurihara, DM Thomson, CL Winchester, A McVie, JR Hedde, AD Randall, S Shen, PA Seymour, ZA Hughes, J Dunlop, JT Brown, NJ Brandon, BJ Morris, JA Pratt

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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 (RT) 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.
Original languageEnglish
Article numbere569
Number of pages12
JournalTranslational Psychiatry
Volume5
DOIs
Publication statusPublished - 19 May 2015

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Transgenic Mice
Glutamic Acid
Brain
Schizophrenia
Prefrontal Cortex
N-Methyl-D-Aspartate Receptors
Genes
Ketamine
Endophenotypes
Neurotransmitter Agents
Animals
Thalamus
Psychiatry

Keywords

  • electrophysiology
  • brain networks
  • ketamine
  • disrupted in schizophrenia 1
  • DISC1
  • disc1tr hemi mice
  • brain connectivity

Cite this

Dawson, N ; Kurihara, M ; Thomson, DM ; Winchester, CL ; McVie, A ; Hedde, JR ; Randall, AD ; Shen, S ; Seymour, PA ; Hughes, ZA ; Dunlop, J ; Brown, JT ; Brandon, NJ ; Morris, BJ ; Pratt, JA. / Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1. In: Translational Psychiatry. 2015 ; Vol. 5.
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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 (RT) 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.",
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author = "N Dawson and M Kurihara and DM Thomson and CL Winchester and A McVie and JR Hedde and AD Randall and S Shen and PA Seymour and ZA Hughes and J Dunlop and JT Brown and NJ Brandon and BJ Morris and JA Pratt",
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Dawson, N, Kurihara, M, Thomson, DM, Winchester, CL, McVie, A, Hedde, JR, Randall, AD, Shen, S, Seymour, PA, Hughes, ZA, Dunlop, J, Brown, JT, Brandon, NJ, Morris, BJ & Pratt, JA 2015, 'Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1', Translational Psychiatry, vol. 5, e569. https://doi.org/10.1038/tp.2015.60

Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1. / Dawson, N; Kurihara, M ; Thomson, DM; Winchester, CL; McVie, A; Hedde, JR; Randall, AD; Shen, S; Seymour, PA; Hughes, ZA; Dunlop, J ; Brown, JT; Brandon, NJ ; Morris, BJ; Pratt, JA.

In: Translational Psychiatry, Vol. 5, e569, 19.05.2015.

Research output: Contribution to journalArticle

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T1 - Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1

AU - Dawson, N

AU - Kurihara, M

AU - Thomson, DM

AU - Winchester, CL

AU - McVie, A

AU - Hedde, JR

AU - Randall, AD

AU - Shen, S

AU - Seymour, PA

AU - Hughes, ZA

AU - Dunlop, J

AU - Brown, JT

AU - Brandon, NJ

AU - Morris, BJ

AU - Pratt, JA

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N2 - 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 (RT) 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.

AB - 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 (RT) 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.

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