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The impact of Disrupted-in-Schizophrenia 1 (DISC1) on the dopaminergic system: A systematic review

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T. Dahoun, S. V. Trossbach, N. J. Brandon, C. Korth, O. D. Howes

Original languageEnglish
Article numbere1015
JournalTranslational psychiatry
Volume7
Issue number1
DOIs
Published2017

Bibliographical note

Funding Information: NJB is a full-time employee and a shareholder in AstraZeneca plc. ODH has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by AstraZeneca, Autifony, BMS, Eli Lilly, Heptares, Jansenn, Lundbeck, Lyden-Delta, Otsuka, Servier, Sunovion, Rand and Roche. The remaining authors declare no conflict of interest. Funding Information: This work was supported by a EU-FP7 MC-ITN IN-SENS grant (grant number 607616) to TD, NJB, CK and ODH, a NARSAD/BBR Independent Investigator Award (grant number 20350) and a grant from the Forschungskommission of the Medical Faculty/ Heinrich Heine University Düsseldorf (#9772569) to CK, a Medical Research Council (UK) grant (grant number MC-A656-5QD30), a Maudsley Charity Grant (grant number 666) and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London to ODH. Publisher Copyright: © The Author(s) 2017. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Disrupted-in-Schizophrenia 1 (DISC1) is a gene known as a risk factor for mental illnesses possibly associated with dopamine impairments. DISC1 is a scaffold protein interacting with proteins involved in the dopamine system. Here we summarise the impact of DISC1 disruption on the dopamine system in animal models, considering its effects on presynaptic dopaminergic function (tyrosine hydroxylase levels, dopamine transporter levels, dopamine levels at baseline and after amphetamine administration) and postsynaptic dopaminergic function (dopamine D1 and D2 receptor levels, dopamine receptor-binding potential and locomotor activity after amphetamine administration). Our findings show that many but not all DISC1 models display (1) increased locomotion after amphetamine administration, (2) increased dopamine levels after amphetamine administration in the nucleus accumbens, and (3) inconsistent basal dopamine levels, dopamine receptor levels and binding potentials. There is also limited evidence for decreased tyrosine hydroxylase levels in the frontal cortex and increased dopamine transporter levels in the striatum but not nucleus accumbens, but these conclusions warrant further replication. The main dopaminergic findings are seen across different DISC1 models, providing convergent evidence that DISC1 has a role in regulating dopaminergic function. These results implicate dopaminergic dysregulation as a mechanism underlying the increased rate of schizophrenia seen in DISC1 variant carriers, and provide insights into how DISC1, and potentially DISC1-interacting proteins such as AKT and GSK-3, could be used as novel therapeutic targets for schizophrenia.

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