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 show potential for the treatment of schizophrenia [5][6][7] . The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide (LSD), 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 via specific transmembrane helix domains with the 2AR, a member of an unrelated G protein-coupled receptor (GPCR) 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 postmortem human brain from untreated schizophrenic subjects, the 2AR is up-regulated and the mGluR2 is down-regulated, a pattern that could predispose to psychosis. These regulatory changes suggest that the 2AR/mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and represents a promising new target for the treatment of psychosis.Correspondence and requests for materials should be addressed to: J.G.M (e-mail: Javier.Maeso@mssm.edu) S.C.S. (e-mail: Stuart.Sealfon@mssm.edu). The 2AR and mGluR2/3 show an overlapping distribution in brain cortex in autoradiography studies 13 . The mGluR2 and mGluR3 are not distinguished by autoradiographic ligands. We used fluorescent in situ hybridization (FISH) to determine whether either of these receptor subtypes are co-expressed by the same neurons. In layer V mouse somatosensory cortex (SCx), 2AR mRNA positive cells were mostly mGluR2 mRNA positive. The level of expression in SCx was much lower for mGluR3 mRNA, which rarely co-localized with 2AR mRNA (Fig. 1a). Control studies validated assay sensitivity and specificity, and similar 2AR/mGluR2 mRNA co-localization was found in cortical primary cultures (Figs. 1a,b,c, and Supplementary Fig. S1). Translation of 2AR protein in cortical pyramidal neurons was found to be necessary for normal mGluR2 expression. Mice with globally disrupted 2AR expression (htr2A−/− mice) showed reduced cortical mGluR2 binding and expression, while mice in which 2AR expression was selectively restored in cortical pyramidal neurons 8,14 showed control expression levels (Supplementary Table S1, and Supplementary Fig. S2). The effects of mGluR2/3 activation on 2AR responses have been generally attributed to synaptic mechanisms 5,6,13,15 . However, the co-localization of 2AR and mGluR2 and the reduction of mGluR2 expression levels in htr2A−/− mice motivated us to examine whether a direct mechanism contributed to cortical crosstalk between these two receptor systems. NIH Public AccessRecent studies have demonstrated that some GPCRs belonging to the same sequence classes can form ...

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