Dataset Information

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.

SUBMITTER: Dawson N

PROVIDER: S-EPMC4471291 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Dawson N N Kurihara M M Thomson D M DM Winchester C L CL McVie A A Hedde J R JR Randall A D AD Shen S S Seymour P A PA Hughes Z A ZA Dunlop J J Brown J T JT Brandon N J NJ Morris B J BJ Pratt J A JA

Translational psychiatry 20150519

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 pr ...[more]

PMID: 25989143

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Project description:Alterations in cortical inter-areal functional connectivity, and aberrant glutamatergic signalling are implicated in the pathophysiology of schizophrenia but the relationship between the two is unclear. We used multimodal imaging to identify areas of convergence between the two systems. Two separate cohorts were examined, comprising 195 participants in total. All participants received resting state functional MRI to characterise functional brain networks and proton magnetic resonance spectroscopy (1H-MRS) to measure glutamate concentrations in the frontal cortex. Study A investigated the relationship between frontal cortex glutamate concentrations and network connectivity in individuals with schizophrenia and healthy controls. Study B also used 1H-MRS, and scanned individuals with schizophrenia and healthy controls before and after a challenge with the glutamatergic modulator riluzole, to investigate the relationship between changes in glutamate concentrations and changes in network connectivity. In both studies the network based statistic was used to probe associations between glutamate and connectivity, and glutamate associated networks were then characterised in terms of their overlap with canonical functional networks. Study A involved 76 individuals with schizophrenia and 82 controls, and identified a functional network negatively associated with glutamate concentrations that was concentrated within the salience network (p < 0.05) and did not differ significantly between patients and controls (p > 0.85). Study B involved 19 individuals with schizophrenia and 17 controls and found that increases in glutamate concentrations induced by riluzole were linked to increases in connectivity localised to the salience network (p < 0.05), and the relationship did not differ between patients and controls (p > 0.4). Frontal cortex glutamate concentrations are associated with inter-areal functional connectivity of a network that localises to the salience network. Changes in network connectivity in response to glutamate modulation show an opposite effect compared to the relationship observed at baseline, which may complicate pharmacological attempts to simultaneously correct glutamatergic and connectivity aberrations.

Project description:From a large clinical blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) study, we report several interrelated findings involving transient supra-network brainwide states characterized by a saturation phenomenon we are referring to as "polarization." These are whole-brain states in which the voxelwise-normalized BOLD (vn-BOLD) activation of a large proportion of voxels is simultaneously either very high or very low. The presence of such states during a resting-state fMRI (rs-fMRI) scan is significantly anti-correlated with diagnosed schizophrenia, significantly anti-correlated with connectivity between subcortical networks and auditory, visual and sensorimotor networks and also significantly anti-correlated with contemporaneous occupancy of transient functional network connectivity states featuring broad disconnectivity or strong inhibitory connections between the default mode and other networks. Conversely, the presence of highly polarized vn-BOLD states is significantly correlated with connectivity strength between auditory, visual and sensorimotor networks and with contemporaneous occupancy of transient whole-brain patterns of strongly modularized network connectivity and diffuse hyperconnectivity. Despite their consistency with well-documented effects of schizophrenia on static and time-varying functional network connectivity, the observed relationships between polarization and network connectivity are with very few exceptions unmediated by schizophrenia diagnosis. Many differences observed between patients and controls are echoed within the patient population itself in the effect patterns of positive symptomology (e.g. hallucinations, delusions, grandiosity). Our findings highlight a particular whole-brain spatiotemporal BOLD activation phenomenon that differs markedly between healthy subjects and schizophrenia patients, one that also strongly informs time-resolved network connectivity patterns that are associated with this serious clinical disorder.

Dataset Information

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

Publications

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

Similar Datasets

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