Altered Signaling in CB1R-5-HT2AR Heteromers in Olfactory Neuroepithelium Cells of Schizophrenia Patients is Modulated by Cannabis Use.
Schizophrenia (SCZ) has been associated with serotonergic and endocannabinoid systems dysregulation, but difficulty in obtaining in vivo neurological tissue has limited its exploration. We investigated CB1R-5-HT2AR heteromer expression and functionality via intracellular pERK and cAMP quantification in olfactory neuroepithelium (ON) cells of SCZ patients non-cannabis users (SCZnc), and evaluated whether cannabis modulated these parameters in patients using cannabis (SCZc). Results were compared vs healthy controls non-cannabis users (HCnc) and healthy controls cannabis users (HCc). Further, antipsychotic effects on heteromer signaling were tested in vitro in HCnc and HCc. Results indicated that heteromer expression was enhanced in both SCZ groups vs HCnc. Additionally, pooling all 4 groups together, heteromer expression correlated with worse attentional performance and more neurological soft signs (NSS), indicating that these changes may be useful markers for neurocognitive impairment. Remarkably, the previously reported signaling properties of CB1R-5-HT2AR heteromers in ON cells were absent, specifically in SCZnc treated with clozapine. These findings were mimicked in cells from HCnc exposed to clozapine, suggesting a major role of this antipsychotic in altering the quaternary structure of the CB1R-5-HT2AR heteromer in SCZnc patients. In contrast, cells from SCZc showed enhanced heteromer functionality similar to HCc. Our data highlight a molecular marker of the interaction between antipsychotic medication and cannabis use in SCZ with relevance for future studies evaluating its association with specific neuropsychiatric alterations.