Y-chromosome in the olfactory neuroepithelium as a potential biomarker of depression in women with male offspring: an exploratory study.

The persistence of fetal cells in the mother (fetal microchimerism (FMc)) has been described in maternal tissues essential to the newborn. FMc is associated with several diseases that start or worsen in pregnancy or postpartum. This exploratory study reports-for the first time-the presence of FMc in the olfactory neuroepithelium (ON) of both healthy and depressed women with male offspring. However, depressed women had fewer microchimeric cells (digital PCR). The existence of FMc in the ON could facilitate mother-child bonding. These findings open new pathways to study FMc in the ON, female depression, and mother-child bonding.

Role of cyclin-dependent kinase 5 in psychosis and the modulatory effects of cannabinoids.

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is altered in treated schizophrenia patients, and cannabinoids modulate CDK5 levels in the brain of rodents. However, the role of this kinase, and its interaction with cannabis use in first-episode psychosis (FEP) patients is still not known. Hence, we studied the expression changes of CDK5 and its signaling partner, postsynaptic density protein 95 (PSD95) in olfactory neuroepithelial (ON) cells of FEP patients with (FEP/c) and without (FEP/nc) prior cannabis use, and in a dual-hit mouse model of psychosis. In this model, adolescent mice were exposed to the cannabinoid receptor 1 agonist (CB1R) WIN-55,212-2 (WIN: 1 mg/kg) during 21 days, and to the N-methyl-d-aspartate receptor (NMDAR) blocker phencyclidine (PCP: 10 mg/kg) during 10 days. FEP/c showed less social functioning deficits, lower CDK5 and higher PSD95 levels than FEP/nc. These changes correlated with social skills, but not cognitive deficits. Consistently, exposure of ON cells from FEP/nc patients to WIN in vitro reduced CDK5 levels. Convergent results were obtained in mice, where PCP by itself induced more sociability deficits, and PSD95/CDK5 alterations in the prefrontal cortex and hippocampus than exposure to PCP-WIN. In addition, central blockade of CDK5 activity with roscovitine in PCP-treated mice restored both sociability impairments and PSD95 levels. We provide translational evidence that increased CDK5 could be an early indicator of psychosis associated with social deficits, and that this biomarker is modulated by prior cannabis use.

Cannabis Use Induces Distinctive Proteomic Alterations in Olfactory Neuroepithelial Cells of Schizophrenia Patients.

A close epidemiological link has been reported between cannabis use and schizophrenia (SCZ). However, biochemical markers in living humans related to the impact of cannabis in this disease are still missing. Olfactory neuroepithelium (ON) cells express neural features and offer a unique advantage to study biomarkers of psychiatric diseases. The aim of our study was to find exclusively deregulated proteins in ON cells of SCZ patients with and without a history of cannabis use. Thus, we compared the proteomic profiles of SCZ non-cannabis users (SCZ/nc) and SCZ cannabis users (SCZ/c) with control subjects non-cannabis users (C/nc) and control cannabis users (C/c). The results revealed that the main cascades affected in SCZ/nc were cell cycle, DNA replication, signal transduction and protein localization. Conversely, cannabis use in SCZ patients induced specific alterations in metabolism of RNA and metabolism of proteins. The levels of targeted proteins in each population were then correlated with cognitive performance and clinical scores. In SCZ/c, the expression levels of 2 proteins involved in the metabolism of RNA (MTREX and ZNF326) correlated with several cognitive markers and clinical signs. Moreover, use duration of cannabis negatively correlated with ZNF326 expression. These findings indicate that RNA-related proteins might be relevant to understand the influence of cannabis use on SCZ.

Olfactory Neuroepithelium Cells from Cannabis Users Display Alterations to the Cytoskeleton and to Markers of Adhesion, Proliferation and Apoptosis.

Cannabis is the third most commonly used psychoactive substance of abuse, yet it also receives considerable attention as a potential therapeutic drug. Therefore, it is essential to fully understand the actions of cannabis in the human brain. The olfactory neuroepithelium (ON) is a peripheral nervous tissue that represents an interesting surrogate model to study the effects of drugs in the brain, since it is closely related to the central nervous system, and sensory olfactory neurons are continually regenerated from populations of stem/progenitor cells that undergo neurogenesis throughout life. In this study, we used ON cells from chronic cannabis users and healthy control subjects to assess alterations in relevant cellular processes, and to identify changes in functional proteomic pathways due to cannabis consumption. The ON cells from cannabis users exhibited alterations in the expression of proteins that were related to the cytoskeleton, cell proliferation and cell death, as well as, changes in proteins implicated in cancer, gastrointestinal and neurodevelopmental pathologies. Subsequent studies showed cannabis provoked an increase in cell size and morphological alterations evident through ß-Tubulin III staining, as well as, enhanced beta-actin expression and a decrease in the ability of ON cells to undergo cell attachment, suggesting abnormalities of the cytoskeleton and cell adhesion system. Furthermore, these cells proliferated more and underwent less cell death. Our results indicate that cannabis may alter key processes of the developing brain, some of which are similar to those reported in mental disorders like DiGeorge syndrome, schizophrenia and bipolar disorder.

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 (SCZ/nc), and evaluated whether cannabis modulated these parameters in patients using cannabis (SCZ/c). Results were compared vs healthy controls non-cannabis users (HC/nc) and healthy controls cannabis users (HC/c). Further, antipsychotic effects on heteromer signaling were tested in vitro in HC/nc and HC/c. Results indicated that heteromer expression was enhanced in both SCZ groups vs HC/nc. 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 SCZ/nc treated with clozapine. These findings were mimicked in cells from HC/nc exposed to clozapine, suggesting a major role of this antipsychotic in altering the quaternary structure of the CB1R-5-HT2AR heteromer in SCZ/nc patients. In contrast, cells from SCZ/c showed enhanced heteromer functionality similar to HC/c. 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.