Cannabis Use Induces Distinctive Proteomic Alterations in Olfactory Neuroepithelial Cells of Schizophrenia Patients.
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ABSTRACT:
SUBMITTER: Barrera-Conde M
PROVIDER: S-EPMC7996288 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this study, we evaluated the common proteomic profile, as well as, the exclusively deregulated proteins in ON cells from healthy controls cannabis users (HC/c), SCZ patients non-cannabis users (SCZ/nc) and SCZ patients cannabis users (SCZ/c) as compared to healthy controls non-cannabis users (HC/nc). Moreover, we investigated quantitative and functional differences between HC/c and SCZ, and we characterized the distinct effect of cannabis in SCZ comparing SCZ/nc and SCZ/c.
2021-09-09 | PXD020739 | Pride
Project description:Increasing evidence suggests that olfactory dysfunction is an endophenotype of schizophrenia, and thus the olfactory system can be studied both in relation to this sensory dysfunction and also as a means of examining pathophysiologic mechanisms of schizophrenia. In this study, we examined human olfactory neuroepithelial (ON) biopsy tissues and their in vitro culture cells for ligand-induced guanine nucleotide-binding protein (G protein) activation and downstream signaling. We assessed the binding of a nonhydrolyzable GTP analogue [(35)S]GTP?S binding to specific G protein subtypes in response to odorants, dopamine, or serotonin in ON cell membranes from matched schizophrenia-control subjects. In response to odorant mixtures, we found decreased [(35)S]GTP?S binding to G?s/olf in schizophrenia patients. These changes were not mediated by mRNA expression of key molecules of G protein coupling, including adenylate cyclase III (ACIII), protein kinase A (PKA), protein kinase C? (PKC?), or G?s or G?olf in ON cells or ON biopsy tissues. In contrast, dopamine (DA)- and serotonin (5HT)-induced S(35)-GTP?S binding to G?s/olf and G?q/11 were significantly increased in schizophrenia cases, while these parameters were strikingly reduced by in vitro treatment with antipsychotics. Patients with schizophrenia exhibit increases in electrolfactogram (EOG) recordings, suggesting enhanced odorant-induced activation. Our results of decreased odorant-induced G protein activation may point further downstream for underlying mechanisms for increased EOG measures. Increased G protein activation in response to DA and 5HT may suggest increased postreceptor DA or 5HT signaling as an additional mechanism of dopaminergic or serotonergic dysregulation in schizophrenia.
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Project description: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.
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Project description:Schizophrenia is associated with alterations in working memory that reflect dysfunction of dorsolateral prefrontal cortex (DLPFC) circuitry. Working memory depends on the activity of excitatory pyramidal cells in DLPFC layer 3 and, to a lesser extent, in layer 5. Although many studies have profiled gene expression in DLPFC gray matter in schizophrenia, little is known about cell-type-specific transcript expression in these two populations of pyramidal cells. We hypothesized that interrogating gene expression, specifically in DLPFC layer 3 or 5 pyramidal cells, would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness. We also sought to determine the impact of other variables, such as a diagnosis of schizoaffective disorder or medication use at the time of death, on the patterns of gene expression in pyramidal neurons. Individual pyramidal cells in DLPFC layers 3 or 5 were captured by laser microdissection from 36 subjects with schizophrenia or schizoaffective disorder and matched normal comparison subjects. The mRNA from cell collections was subjected to transcriptome profiling by microarray followed by quantitative PCR validation. Expression of genes involved in mitochondrial (MT) or ubiquitin-proteasome system (UPS) functions were markedly downregulated in the patient group (P-values for MT-related and UPS-related pathways were <10(-7) and <10(-5), respectively). MT-related gene alterations were more prominent in layer 3 pyramidal cells, whereas UPS-related gene alterations were more prominent in layer 5 pyramidal cells. Many of these alterations were not present, or found to a lesser degree, in samples of DLPFC gray matter from the same subjects, suggesting that they are pyramidal cell specific. Furthermore, these findings principally reflected alterations in the schizophrenia subjects were not present or present to a lesser degree in the schizoaffective disorder subjects (diagnosis of schizoaffective disorder was the most significant covariate, P<10(-6)) and were not attributable to factors frequently comorbid with schizophrenia. In summary, our findings reveal expression deficits in MT- and UPS-related genes specific to layer 3 and/or layer 5 pyramidal cells in the DLPFC of schizophrenia subjects. These cell type-specific transcriptome signatures are not characteristic of schizoaffective disorder, providing a potential molecular-cellular basis of differences in clinical phenotypes.
| S-EPMC4492919 | biostudies-literature
Project description:Schizophrenia is associated with alterations in working memory that reflect dysfunction of dorsolateral prefrontal cortex (DLPFC) circuitry. Working memory depends on the activity of excitatory pyramidal cells in DLPFC layer 3, and to a lesser extent in layer 5. Although many studies have profiled gene expression in DLPFC gray matter in schizophrenia, little is known about cell type-specific transcript expression in these two populations of pyramidal cells. We hypothesized that interrogating gene expression specifically in DLPFC layer 3 or 5 pyramidal cells would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness.
2017-07-23 | GSE93987 | GEO
Project description:Cannabis use is observationally associated with an increased risk of schizophrenia, but whether the relationship is causal is not known. Using a genetic approach, we took 10 independent genetic variants previously identified to associate with cannabis use in 32 330 individuals to determine the nature of the association between cannabis use and risk of schizophrenia. Genetic variants were employed as instruments to recapitulate a randomized controlled trial involving two groups (cannabis users vs nonusers) to estimate the causal effect of cannabis use on risk of schizophrenia in 34 241 cases and 45 604 controls from predominantly European descent. Genetically-derived estimates were compared with a meta-analysis of observational studies reporting ever use of cannabis and risk of schizophrenia or related disorders. Based on the genetic approach, use of cannabis was associated with increased risk of schizophrenia (odds ratio (OR) of schizophrenia for users vs nonusers of cannabis: 1.37; 95% confidence interval (CI), 1.09-1.67; P-value=0.007). The corresponding estimate from observational analysis was 1.43 (95% CI, 1.19-1.67; P-value for heterogeneity =0.76). The genetic markers did not show evidence of pleiotropic effects and accounting for tobacco exposure did not alter the association (OR of schizophrenia for users vs nonusers of cannabis, adjusted for ever vs never smoker: 1.41; 95% CI, 1.09-1.83). This adds to the substantial evidence base that has previously identified cannabis use to associate with increased risk of schizophrenia, by suggesting that the relationship is causal. Such robust evidence may inform public health messages about cannabis use, especially regarding its potential mental health consequences.
| S-EPMC5984096 | biostudies-literature
Project description:Cannabis use has been growing recently and it is legally consumed in many countries. Cannabis has a variety of phytochemicals including cannabinoids, which might impair the peripheral systems responses affecting inflammatory and immunological pathways. However, the exact signaling pathways that induce these effects need further understanding. The objective of this study is to investigate the serum proteomic profiling in patients diagnosed with cannabis use disorder (CUD) as compared with healthy control subjects. The novelty of our study is to highlight the differentially changes proteins in the serum of CUD patients. Certain proteins can be targeted in the future to attenuate the toxicological effects of cannabis. Blood samples were collected from 20 male individuals: 10 healthy controls and 10 CUD patients. An untargeted proteomic technique employing two-dimensional difference in gel electrophoresis coupled with mass spectrometry was employed in this study to assess the differentially expressed proteins. The proteomic analysis identified a total of 121 proteins that showed significant changes in protein expression between CUD patients (experimental group) and healthy individuals (control group). For instance, the serum expression of inactive tyrosine protein kinase PEAK1 and tumor necrosis factor alpha-induced protein 3 were increased in CUD group. In contrast, the serum expression of transthyretin and serotransferrin were reduced in CUD group. Among these proteins, 55 proteins were significantly upregulated and 66 proteins significantly downregulated in CUD patients as compared with healthy control group. Ingenuity pathway analysis (IPA) found that these differentially expressed proteins are linked to p38MAPK, interleukin 12 complex, nuclear factor-κB, and other signaling pathways. Our work indicates that the differentially expressed serum proteins between CUD and control groups are correlated to liver X receptor/retinoid X receptor (RXR), farnesoid X receptor/RXR activation, and acute phase response signaling.
| S-EPMC8434053 | biostudies-literature
Project description:Chronic cannabis use and schizophrenia are both thought to affect reward processing. While behavioural and neural effects on reward processing have been investigated in both conditions, their interaction has not been studied, although chronic cannabis use is common among these patients. In the present study eighty-nine participants divided into four groups (control chronic cannabis users and non-users; schizophrenia patient cannabis users and non-users) performed a two-choice decision task, preceded by monetary cues (high/low reward/punishment or neutral), while being scanned using functional magnetic resonance imaging. Reward and punishment anticipation resulted in activation of regions of interest including the thalamus, striatum, amygdala and insula. Chronic cannabis use and schizophrenia had opposing effects on reward anticipation sensitivity. More specifically control users and patient non-users showed faster behavioural responses and increased activity in anterior/posterior insula for high magnitude cues compared to control non-users and patient users. The same interaction pattern was observed in the activation of the right thalamus for reward versus punishment cues. This study provided evidence for interaction of chronic cannabis use and schizophrenia on reward processing and highlights the need for future research addressing the significance of this interaction for the pathophysiology of these conditions and its clinical consequences.
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Project description:Background:Cannabis is the second most used recreational drug in the United States and one of the most used substances in patients with schizophrenia spectrum disorder (SSD). Unfortunately, the increased use is likely to continue as more states legalize recreational use of cannabis. Although the association between cannabis and schizophrenia has been studied extensively, the understanding of the relationship is still evolving. In this study, we sought to determine the prevalence and potential factors associated with cannabis use (CU) among inpatients with SSD at a community teaching hospital. Methods:We performed a retrospective review of the electronic medical charts of patients discharged from the psychiatric unit of our hospital from July 1, 2017 through October 31, 2017. Patients were included in this study if: 1) They were ? 18 years old; 2) They had discharge diagnosis of SSD; and 3) They had urine drug testing performed. Pertinent sociodemographic and clinical variables, including substance use status and hospital length of stay (LOS), were abstracted. Univariate frequencies and summary statistics were performed. Odds ratios (ORs) were determined by logistic regression analysis of bivariate and multivariate analyses. Results:Three hundred sixty-five (52.2%) patients had a discharge diagnosis of SSD, and only 322 had urine toxicology result for cannabinoids and were included in analysis. Of the 322 patients, 41.5% (n = 133) screened positive for cannabinoids. Of the 133 patients, 78% were African American, 15% were Hispanic and 5% were White; 77% were male and the median age was 36 years. Bivariate analyses showed tobacco use (OR: 2.8, 95% confidence interval (CI): 1.7 - 4.6), alcohol use (OR: 3.4, 95% CI: 2.9 - 7.0), younger age (OR: 2.8, 95% CI: 1.8 - 4.5), male gender (OR: 2.9, 95% CI: 2.2 - 3.2), unemployment (OR: 3.91, 95% CI: 3.49 - 7.35), homelessness (OR: 3.18, 95% CI: 2.76 - 3.84) and LOS (OR: 3.46, 95% CI: 2.93 - 4.31) were significantly associated with CU. Result of multivariate analysis was similar to that found in bivariate analysis. Conclusions:CU appears to be prevalent among patients with SSD. Clinicians and public health professionals are encouraged to understand the health implications of its use in patients with mental illness especially against the backdrop of current marijuana laws.
| S-EPMC7188370 | biostudies-literature
Project description:Frequent cannabis use during adolescence has been associated with alterations in brain structure. However, studies have featured relatively inconsistent results, predominantly from small samples, and few studies have examined less frequent users to shed light on potential brain structure differences across levels of cannabis use. In this study, high-resolution T1-weighted MRIs were obtained from 781 youth aged 14-22 years who were studied as part of the Philadelphia Neurodevelopmental Cohort. This sample included 147 cannabis users (109 occasional [≤1-2 times per week] and 38 frequent [≥3 times per week] users) and 634 cannabis non-users. Several structural neuroimaging measures were examined in whole brain analyses, including gray and white matter volumes, cortical thickness, and gray matter density. Established procedures for stringent quality control were conducted, and two automated neuroimaging software processing packages were used to ensure robustness of results. There were no significant differences by cannabis group in global or regional brain volumes, cortical thickness, or gray matter density, and no significant group by age interactions were found. Follow-up analyses indicated that values of structural neuroimaging measures by cannabis group were similar across regions, and any differences among groups were likely of a small magnitude. In sum, structural brain metrics were largely similar among adolescent and young adult cannabis users and non-users. Our data converge with prior large-scale studies suggesting small or limited associations between cannabis use and structural brain measures in youth. Detailed studies of vulnerability to structural brain alterations and longitudinal studies examining long-term risk are clearly indicated.
| S-EPMC6784999 | biostudies-literature