دانلود رایگان ترجمه مقاله اثر اختلال در اسکیزوفرنی 1 (DISC1) بر سیستم دوپامینرژیک – NATURE 2017

اثر اختلال در اسکیزوفرنی 1 (DISC1) بر سیستم دوپامینرژیک: بررسی سیستماتیک

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.

1 Introduction

The Disrupted-in-Schizophrenia 1 (DISC1) gene was originally discovered at the breakpoint of a balanced translocation t(1;11) (q42;q14.3) in a Scottish family and later identified in a North American family with high rates of schizophrenia.1–4 Since then, preclinical models have shown that DISC1 mutant animals exhibit behavioural, neurostructural and neurochemical features relevant to schizophrenia, 5,6 although its significance for the human disease has been debated.7–9 DISC1 is described as a scaffold protein with multiple interactors involved in a wide range of cellular processes including neurotransmitter signalling.10,11 In particular, DISC1 is known to interact with several proteins involved in dopamine signalling including fasciculation and elongation protein zeta 1, phosphodiesterase 4D9 and phosphodiesterase 4B, serine/threonine protein kinase Akt and glycogen synthase kinase-3 (GSK-3)12–16 as well as synaptic interactors such as kalirin7 and the Traf2, Nck-interacting kinase,17,18 and the microtubule/ centrosomal proteins pericentriolar material 1 and Bardet–Biedl syndrome protein.19,20 These multiple interactions have highlighted the potential of DISC1 as a therapeutic target.21–23 The neurotransmitter dopamine is widely thought to have a central role in the aetiology of psychotic disorders.24–26 The dopamine hypothesis of schizophrenia was initially based on the findings that the affinity of antipsychotic medications for dopamine receptors is closely related to their clinical potency,27–29 and that drugs that increase dopamine levels provoke psychotic symptoms in healthy people.30,31 Molecular imaging studies since then have shown increased presynaptic dopamine synthesis capacity and release in schizophrenia32–35 and in subjects with prodromal symptoms of schizophrenia.36–39 Alterations in dopamine D1 and D2/3 receptors, tyrosine hydroxylase (TH) levels and baseline synaptic dopamine levels in schizophrenia have also been reported,40,41 although with some inconsistency.42 These findings highlight why dopaminergic dysfunction has a pivotal role in schizophrenia. In view of this, we sought to review the evidence from animal models that DISC1 pathway alterations may impact on dopaminergic function, as it has not been comprehensively synthesised before. The aim of our review was therefore to summarise the impact of DISC1 on TH levels, dopamine transporter (DAT) levels, basal dopamine levels and after amphetamine administration, dopamine D2 receptor-binding potential (BP), dopamine D1 (D1R) and D2 receptor (D2R) levels, and locomotor activity after amphetamine administration for dopamine-related behaviour.43 We selected publications citing data collection in the midbrain, as this is the location of the majority of dopaminergic neuron cell bodies in the brain, and the frontal cortex, hippocampus and striatum as these are the target sites of the main dopaminergic pathways relevant to psychiatric disorders.

MATERIALS AND METHODS

Selection of studies

The entire PubMed database was searched to select publications. Studies were screened based on the terms (‘Disrupted-inSchizophrenia-1’ OR ‘DISC1’) AND (‘dopamine’ OR ‘tyrosine hydroxylase’ OR ‘dopamine receptor’ OR ‘DAT’ OR ‘amphetamine’ OR ‘behavioral alterations’ OR ‘locomotor activity’ OR ‘Positron Emission Tomography’ OR ‘PET’ OR ‘Single Photon Emission Computed Tomography’ OR ‘SPECT’). Only articles meeting the following criteria were included: (1) original studies; (2) English language; (3) peer-review journals; (4) findings reporting TH levels, DAT levels, basal dopamine levels and/or dopamine levels after amphetamine administration, and/or dopamine receptor-binding potential, dopamine receptor levels and/or locomotion after amphetamine administration in a DISC1 model compared with a control group; and (5) in the frontal cortex, striatum, nucleus accumbens, midbrain and/or hippocampus, as these regions are major target sites of dopaminergic projections in the brain and are thought to be involved in the pathophysiology of schizophrenia.44,45 The DISC1 models were selected based on gene mutation in DISC1 or alteration in the quantitative expression of DISC1 protein. Method and results sections of the eligible articles were screened to identify the measures of interest listed above.

Data extraction

The main outcome measures were the differences between the DISC1 models and controls in (1) TH levels; (2) DAT levels; (3) basal dopamine levels; (4) dopamine levels after amphetamine administration; (5) dopamine receptor-binding potential; (6) D1R and D2R levels; and (7) locomotion after amphetamine administration. In addition, the following data were extracted: (8) authors; (9) year of publication; (10) the DISC1 model; (11) samples size; and (12) methods. The data were extracted by TD and checked by SVT. Findings related to the nucleus accumbens and olfactory tubercle were merged as both being part of the ventral striatum.46