Neuron
Volume 84, Issue 6, 17 December 2014, Pages 1302-1316
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Article
A Dopamine D2 Receptor-DISC1 Protein Complex may Contribute to Antipsychotic-Like Effects

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Highlights

  • D2R-DISC1 complex is increased in postmortem brain from schizophrenia patients

  • GSK-3α/β phosphorylation is also decreased in postmortem brain of these patients

  • Activation of D2R enhances D2R-DISC1 coupling and reduces GSK-3α/β phosphorylation

  • Disrupting the D2R-DISC1 complex has antipsychotic-like effects without EPS in vivo

Summary

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.

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