Our final goal is to mechanistically characterize the essential role of the serotonin 5-HT2A (5HT2A) receptor and the metabotropic glutamate 2 (mGlu2) receptor as a G protein-coupled receptor (GPCR) heteromeric complex in regulating receptor trafficking, signaling, and antipsychotic-like behavior. The neurotransmitters serotonin and glutamate both have been the target of considerable attention regarding psychosis and antipsychotic drug development. Family A 5HT2A and family C mGlu2 are GPCRs that have been implicated in the pathophysiology and treatment of schizophrenia and other psychotic disorders. Atypical antipsychotic drugs, such as clozapine, olanzapine and risperidone, all have in common a high affinity for the 5HT2A receptor. Recent preclinical assays in rodents suggest that drugs that activate the mGlu2 receptor represent potential new antipsychotic medications. Our previous findings demonstrate that 5HT2A and mGlu2 maintain close molecular proximity in heterologous systems and in mouse frontal cortex. Using the combination of interdisciplinary approaches in vitro, in animal models and in postmortem human brain of schizophrenic subjects, we provide evidence that the 5HT2A-mGlu2 heteromeric receptor complex is necessary for the therapeutic responses induced by atypical and glutamate antipsychotic drugs, and is potentially involved in the altered cortical processes of schizophrenia. In order to provide a better understanding of the 5HT2A-mGlu2 complex in brain function, and the foundation for the development of more effective antipsychotic drugs, we propose to characterize the basic molecular mechanisms involved in its intracellular trafficking and signaling, as well as to investigate the antipsychotic-like behavioral responses that require expression of 5HT2A and mGlu2 as a GPCR heteromer in mouse. Our results are expected to extend our understanding of the molecular basis of psychosis, and may provide a route to the identification of new and more effective drugs for the treatment of schizophrenia and other psychotic disorders.

Public Health Relevance

Schizophrenia is a chronic mental disorder that affects approximately one percent of the population worldwide, with similar prevalence throughout diverse cultures and geographic areas. We have discovered that two neurotransmitter receptors are expressed in close molecular proximity in the brain, and that this receptor complex is affected in schizophrenia brain. A better understanding of the structure and behavioral function of the neuroreceptor complex may lead to the identification of more effective therapeutic approaches for the treatment of schizophrenia and other psychiatric disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
High Priority, Short Term Project Award (R56)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Nadler, Laurie S
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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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
Moreno, José L; Miranda-Azpiazu, Patricia; García-Bea, Aintzane et al. (2016) Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Sci Signal 9:ra5
Ibi, Daisuke; González-Maeso, Javier (2015) Epigenetic signaling in schizophrenia. Cell Signal 27:2131-6
Kurita, Mitsumasa; Moreno, José L; Holloway, Terrell et al. (2013) Repressive epigenetic changes at the mGlu2 promoter in frontal cortex of 5-HT2A knockout mice. Mol Pharmacol 83:1166-75