title: The impact of Disrupted-in-Schizophrenia 1 (DISC1) on the dopaminergic system: a systematic review.
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.
authors.affiliation: Psychiatric Imaging Group MRC London Institute of Medical Sciences, Hammersmith Hospital, London, UK.|Institute of Clinical Sciences, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, UK.|Department of the Institute of Clinical Sciences, Psychiatric Imaging Group, MRC London Institute of Medical Sciences (LMS), Imperial College-Hammersmith Hospital Campus, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Dahoun
authors.affiliation: Department of Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: S V
authors.initials: SV
authors.lastname: Trossbach
authors.affiliation: AstraZeneca Neuroscience, Innovative Medicines and Early Development Biotech Unit, R&D Boston, Waltham, MA, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: Department of Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Korth
authors.affiliation: Psychiatric Imaging Group MRC London Institute of Medical Sciences, Hammersmith Hospital, London, UK.|Institute of Clinical Sciences, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, UK.|Department of the Institute of Clinical Sciences, Psychiatric Imaging Group, MRC London Institute of Medical Sciences (LMS), Imperial College-Hammersmith Hospital Campus, London, UK.|Department of Psychosis Studies, Institute of Psychiatry, Neurology and Neuroscience (IoPPN), King's College London, London, UK.
authors.forename: O D
authors.initials: OD
authors.lastname: Howes
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C498794:Disc1 protein, mouse; C498795:Disc1 protein, rat; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D009419:Nerve Tissue Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine