One of the guiding objectives of modern schizophrenia research is to build a bridge from molecular and cellular biology to the clinical symptoms of this psychotic mental disorder. Monoaminergic neurotransmitters have been the principal focus of schizophrenia research for many decades. Several approaches have also linked the neurotransmitter glutamate to the neurochemical alterations in patients with schizophrenia. Notably, clozapine and other atypical antipsychotics have high affinity for serotonin 5-HT2A receptors (2AR), and metabotropic glutamate receptors 2/3 (mGluR2/3) agonists have recently shown efficacy in treating schizophrenia. We identify a novel and unexpected functional brain 2AR/mGluR2 receptor complex that may unify the anti- serotonin and glutamatergic therapies of schizophrenia. Our results based on in vitro, animal models and postmortem human brain of schizophrenic subjects suggest that this 2AR/mGluR2 complex may be responsible for some psychotic symptoms in schizophrenia, and that it is the direct target of these two different classes of antipsychotic drugs. In order to understand the role of the 2AR/mGluR2 complex in brain function and to set the stage for future drug development we will pursue two aims. We will use in vitro studies in conjunction with cutting-edge computational approaches to investigate the molecular determinants at the interaction interface responsible for 2AR/mGluR2 complex stabilization and functional crosstalk. In cortical primary cultures and in vivo in mouse models we will study the neuronal signaling and behavior dependent on 2AR/mGluR2 complex function. Results of the proposed studies have the potential to provide a greater understanding of the structure and function of the 2AR/mGluR2 complex than is currently available for any G protein-coupled receptor heterocomplex, and may provide the basis for new pharmacological approaches to the treatment of schizophrenia.

Public Health Relevance

Schizophrenia is a chronic, debilitating psychotic mental disorder that affects about one percent of the population in the U.S.A., and the seventh most costly medical illness to our society. We have discovered a new neuroreceptor complex that induces hallucinations in mouse, and is affected in schizophrenia brain. The characterization of the structure of the neuroreceptor will extend our understanding of the molecular basis of psychosis, and may provide a route to the development of new, more effective drugs for the treatment of schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZRG1-MDCN-B (91))
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Nadler, Laurie S
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
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Mato, Susana; Pilar-Cuéllar, Fuencisla; Valdizán, Elsa M et al. (2018) Selective up-regulation of cannabinoid CB1 receptor coupling to Go-proteins in suicide victims with mood disorders. Biochem Pharmacol 157:258-265
de la Fuente Revenga, Mario; Ibi, Daisuke; Saunders, Justin M et al. (2018) HDAC2-dependent Antipsychotic-like Effects of Chronic Treatment with the HDAC Inhibitor SAHA in Mice. Neuroscience 388:102-117
Ma, Sai; de la Fuente Revenga, Mario; Sun, Zhixiong et al. (2018) Cell-type-specific brain methylomes profiled via ultralow-input microfluidics. Nat Biomed Eng 2:183-194
Fomsgaard, Luna; Moreno, Jose L; de la Fuente Revenga, Mario et al. (2018) Differences in 5-HT2A and mGlu2 Receptor Expression Levels and Repressive Epigenetic Modifications at the 5-HT2A Promoter Region in the Roman Low- (RLA-I) and High- (RHA-I) Avoidance Rat Strains. Mol Neurobiol 55:1998-2012
Mitchell, A C; Javidfar, B; Pothula, V et al. (2018) MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice. Mol Psychiatry 23:123-132
Hideshima, Kelsey S; Hojati, Ashkhan; Saunders, Justin M et al. (2018) Role of mGlu2 in the 5-HT2A receptor-dependent antipsychotic activity of clozapine in mice. Psychopharmacology (Berl) :
López-Giménez, Juan F; González-Maeso, Javier (2018) Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways. Curr Top Behav Neurosci 36:45-73
Lopez-Gimenez, Juan F; de la Fuente Revenga, Mario; Ruso-Julve, Fulgencio et al. (2017) Validation of schizophrenia gene expression profile in a preclinical model of maternal infection during pregnancy. Schizophr Res 189:217-218
Fribourg, Miguel; Logothetis, Diomedes E; González-Maeso, Javier et al. (2017) Elucidation of molecular kinetic schemes from macroscopic traces using system identification. PLoS Comput Biol 13:e1005376
Gaitonde, Supriya A; González-Maeso, Javier (2017) Contribution of heteromerization to G protein-coupled receptor function. Curr Opin Pharmacol 32:23-31

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