1. Department of Neurology,
2. Department of Psychiatry,
3. Department of Structural and Chemical Biology and,
4. Center for Translational Systems Biology, Mount Sinai School of Medicine, New York, New York 10029, USA
5. Department of Psychiatry,
6. Sackler Institute Laboratories and,
7. Lieber Center for Schizophrenia Research, Columbia University, and the New York State Psychiatric Institute, New York, New York 10032, USA
8. Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
9. CIBER of Mental Health, and,
10. Department of Pharmacology, University of the Basque Country, E-48940 Leioa, Bizkaia, Spain

Correspondence to: Javier González-Maeso^1,2Stuart C. Sealfon^1,4 Correspondence and requests for materials should be addressed to J.G.M. (Email: javier.maeso@mssm.edu) or S.C.S. (Email: stuart.sealfon@mssm.edu).

Abstract

The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception^{1, 2}. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT_2A receptors (2AR)^{3, 4}. Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia^{5, 6, 7}. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR^{8, 9, 10} and resemble some of the core symptoms of schizophrenia^{10, 11, 12}. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR–mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR–mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.

1. Department of Neurology,
2. Department of Psychiatry,
3. Department of Structural and Chemical Biology and,
4. Center for Translational Systems Biology, Mount Sinai School of Medicine, New York, New York 10029, USA
5. Department of Psychiatry,
6. Sackler Institute Laboratories and,
7. Lieber Center for Schizophrenia Research, Columbia University, and the New York State Psychiatric Institute, New York, New York 10032, USA
8. Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
9. CIBER of Mental Health, and,
10. Department of Pharmacology, University of the Basque Country, E-48940 Leioa, Bizkaia, Spain

Correspondence to: Javier González-Maeso^1,2Stuart C. Sealfon^1,4 Correspondence and requests for materials should be addressed to J.G.M. (Email: javier.maeso@mssm.edu) or S.C.S. (Email: stuart.sealfon@mssm.edu).

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