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Author Notes:

Correspondence: Professor C Korth, Neurodegeneration Unit, Department Neuropathology, University of Düsseldorf Medical School, Moorenstrasse 5, 40225 Düsseldorf, Germany. E-mail: ckorth@hhu.de.

SV Trossbach and V Bader contributed equally to this work.

We thank Franziska Wedekind for excellent technical assistance and helpful discussions regarding autoradiography. We thank Thomas Guillot for construction of the fast-scan cyclic voltammetry system, and members of the HHU Animal Facility for technical assistance.

The authors declare no conflict of interest.


Research Funding:

CK was supported by grants from the Deutsche Forschungsgemeinschaft (Ko1679/3-1, 4/1), NEURON-ERANET DISCover (BMBF 01EW1003), a NARSAD/BBR Independent Investigator Award (#20350), and EU-FP7 MC-ITN IN-SENS (#607616).

FL was supported by the Canadian Institutes for Health Research.

Pamela O'Rorke, Desmond O'Rorke, and Janet Marsh Frosst supported PS work in memory of John William Medland.

AM-S was supported by a grant from the Forschungskommission of the Heinrich-Heine University Düsseldorf Medical Faculty (54/2013).

MA de Souza Silva was supported by a Heisenberg Fellowship SO 1032/5-1 and EU-FP7 (MC-ITN-IN-SENS- #607616).

JPH was supported by NEURON-ERANET DISCover. NIH Grants ES019776 (GWM), NS084739 (KML), DA037653 and ES012870 to (KAS).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Neurosciences
  • Psychiatry
  • Neurosciences & Neurology

Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits

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Journal Title:

Molecular Psychiatry


Volume 21, Number 11


, Pages 1561-1572

Type of Work:

Article | Final Publisher PDF


Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.

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© 2016 Macmillan Publishers Limited, part of Springer Nature.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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