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Neuron. 2014 Dec 17;84(6):1302-16. doi: 10.1016/j.neuron.2014.11.007. Epub 2014 Nov 26.

A dopamine D2 receptor-DISC1 protein complex may contribute to antipsychotic-like effects.

Author information

1
Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
2
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
3
Department of Physiology & Pharmacology, University of Western Ontario, London, ON N6A 5 K8, Canada.
4
Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Departments of Psychology, Toronto, ON M5S 2J7, Canada; Psychiatry, University of Toronto, Toronto, ON M5S 2J7, Canada.
5
Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Psychiatry, University of Toronto, Toronto, ON M5S 2J7, Canada.
6
Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Psychiatry, University of Toronto, Toronto, ON M5S 2J7, Canada. Electronic address: f.liu.a@utoronto.ca.

Abstract

Current antipsychotic drugs primarily target dopamine D2 receptors (D2Rs), in conjunction with other receptors such as those for serotonin. However, these drugs have serious side effects such as extrapyramidal symptoms (EPS) and diabetes. Identifying a specific D2R signaling pathway that could be targeted for antipsychotic effects, without inducing EPS, would be a significant improvement in the treatment of schizophrenia. We report here that the D2R forms a protein complex with Disrupted in Schizophrenia 1 (DISC1) that facilitates D2R-mediated glycogen synthase kinase (GSK)-3 signaling and inhibits agonist-induced D2R internalization. D2R-DISC1 complex levels are increased in conjunction with decreased GSK-3α/β (Ser21/9) phosphorylation in both postmortem brain tissue from schizophrenia patients and in Disc1-L100P mutant mice, an animal model with behavioral abnormalities related to schizophrenia. Administration of an interfering peptide that disrupts the D2R-DISC1 complex successfully reverses behaviors relevant to schizophrenia but does not induce catalepsy, a strong predictor of EPS in humans.

PMID:
25433637
DOI:
10.1016/j.neuron.2014.11.007
[Indexed for MEDLINE]
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