Projects and Grants

Structure and function of the 5-HT2A-mGlu2 receptor heteromer

Family A serotonin 5-HT2A and family C mGlu2 receptors have been implicated in the pathophysiology of schizophrenia and other psychiatric disorders. We have shown that the 5-HT2A receptor and the mGlu2 receptor form a specific GPCR heteromeric complex through which serotonin and glutamate ligands modulate the pattern of G protein coupling in living cells. The objectives related to this project are:

• Minimal oligomeric functional unit of the 5-HT2A-mGlu2 receptor complex
  
• Residues and domains responsible for stabilizing its quaternary structure
  
• G protein-coupling and neuronal signaling pathways modulated specifically by the 5-HT2A-mGlu2 receptor complex
  
• Behavioral responses in mouse models that require expression of 5-HT2A and mGlu2 as a GPCR heteromer
  
• Biochemical assays in postmortem human brain

Role of prenatal environment in the etiology of schizophrenia

Epidemiological studies have indicated that adverse life events that occurred during pregnancy, such as viral infection and severe stress, increase the risk of schizophrenia in the adult offspring. However, the molecular alterations responsible for the neuropsychiatric symptoms induced by maternal adverse life events during pregnancy are as yet not fully understood. Using mouse models of influenza virus infection and variable stress, we are investigating the biochemical and epigenetic alterations induced by maternal/fetal environmental factors that lead to schizophrenia-like behavior in the adult offspring.

Mechanism of action of antipsychotic drugs

Both first generation (or typical) and second generation (or atypical) antipsychotic drugs were discovered as secondary effects of drugs tested for different therapeutic targets. For instance, the first antipsychotic chlorpromazine was discovered in 1952 as an antihistaminic which appeared to decrease psychosis. Haloperidol was originally designed as a pain reliever, and clozapine was described in 1958 as “tricyclic antidepressant with antipsychotic properties”. To date, both the mechanism of action of antipsychotics and the pathogenesis of the disease remain largely unknown. We identified a pattern of cellular signaling that predicts the therapeutic efficacy of new antipsychotic compounds. Studies are being conducted to elucidate the molecular mechanism through which antipsychotic drugs achieve their therapeutic effects.