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Identification of a serotonin/glutamate receptor complex implicated in psychosis

Abstract

The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception1,2. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR)3,4. Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia5,6,7. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR8,9,10 and resemble some of the core symptoms of schizophrenia10,11,12. 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.

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Figure 1: 2AR and mGluR2 co-localize and interact.
Figure 2: mGluR2 transmembrane domains 4/5 mediate association with 2AR.
Figure 3: 2AR–mGluR2 complex-dependent modulation of cellular and behavioural responses.
Figure 4: 2AR is increased and mGluR2 is decreased in schizophrenia.

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Acknowledgements

We thank L. Devi and L. Ivic for critiquing the manuscript; S. Morgello and the Manhattan HIV Brain Bank for providing control brain cortex; I. Rodil, L. Urigüen and B. Lin for assistance with biochemical assays; the Mount Sinai Microscopy and Microarray, Real-Time PCR and Bioinformatics Shared Research Facilities; the staff members of the Basque Institute of Legal Medicine for their cooperation in the study; J. H. Prather for a gift of LY379268; and J.-P. Pin for providing the signalling peptide sequence of rat mGluR5. This study was supported by the National Institutes of Health, UPV/EHU and the Basque Government, the Spanish Ministry of Health, the REM-TAP Network, the Whitehall Foundation, the Gatsby Foundation and the American Foundation for Suicide Prevention.

Author Contributions J.G.M. and S.C.S. designed experiments, supervised research and wrote the manuscript. J.G.M. performed experiments. R.L.A. performed BRET experiments. T.Y. designed and cloned receptor chimaeras. Y.O. assisted with experiments. P.C. performed FISH studies. N.V.W. and M.Z., supervised by J.A.G., performed behaviour experiments and developed mutant mouse lines. J.L.G., supervised by G.M., performed FRET experiments. M.F. performed computer modelling. L.F.C. and J.J.M. performed schizophrenia post-mortem human brain studies. All authors discussed the results and commented on the manuscript.

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Correspondence to Javier González-Maeso or Stuart C. Sealfon.

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The file contains Supplementary Methods with additional references, Supplementary Tables S1-S12, and Supplementary Figures S1-S14 with Legends. (PDF 12531 kb)

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González-Maeso, J., Ang, R., Yuen, T. et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452, 93–97 (2008). https://doi.org/10.1038/nature06612

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