Differential Methylation Pattern of Schizophrenia Candidate Genes in Tetrahydrocannabinol-Consuming Treatment-Resistant Schizophrenic Patients Compared to Non-Consumer Patients and Healthy Controls

Abstract

<b><i>Background:</i></b> Patients suffering from schizophrenic psychosis show reduced synaptic connectivity compared to healthy individuals. Furthermore, the use of cannabis often precedes the onset of schizophrenic psychosis. Therefore, we investigated whether consumption of cannabis has an impact on the methylation pattern of schizophrenia candidate genes concerned with the development and preservation of synapses and synaptic function. <b><i>Methods:</i></b> Fifty blood samples of outpatients affected by treatment-resistant schizophrenic psychosis were collected in the outpatient department of Ch Ste Anne/INSERM (Paris, France). Extracted DNA was sent to the LMN/MHH (Hanover, Germany) where DNA samples were bisulfite converted. The methylation patterns of the promoter region of neuregulin 1 (<i>NRG1</i>), neurexin (<i>NRXN1</i>), disrupted in schizophrenia 1 (<i>DISC1</i>), and microtubule-associated-protein tau (<i>MAPT</i>) were then analysed by sequencing according to Sanger. <b><i>Results:</i></b> In <i>NRXN1</i> the group of non-consumer patients showed a methylation rate slightly lower than controls. In patients with preliminary use of tetrahydrocannabinol (THC) the <i>NRXN1</i> promoter turned out to be methylated almost two times higher than in non-consumer patients. In <i>MAPT</i>, non-consumer patients showed a significant lower mean methylation rate in comparison to controls. In THC-consuming patients the difference compared with controls became less. <i>NRG1</i> and <i>DISC1</i> showed no significant differences between groups, whereas <i>DISC1</i> appeared to be not methylated at all. <b><i>Conclusion:</i></b> In <i>MAPT</i> and <i>NRXN1</i> mean methylation rates were lower in non-consumer patients compared with controls, which seems to be a compensatory mechanism. With consumption of THC, mean methylation rates were increased: in the case of <i>MAPT</i> compared with controls, and in <i>NRXN1</i> even significantly beyond that. Methylation of <i>NRG1</i> and <i>DISC1</i> seems not to be affected by the psychiatric disorder or by consumption of THC.

Neurexins in autism and schizophrenia—a review of patient mutations, mouse models and potential future directions

“…neurodevelopmental disorders [78][79][80]; not only in patients with rare variants as described here but also in non-carrier patients following environmental stressors, such as drug abuse [81][82][83][84][85][86]. The recent GWAS conducted on SCZ patients also revealed genes acting directly on NRXN transcriptomics, such as miR-137 which is predicted to directly target NRXN isoforms [87,88].…”

Changes in Expression of DNA-Methyltransferase and Cannabinoid Receptor mRNAs in Blood Lymphocytes After Acute Cannabis Smoking

“…These lines of evidence suggest that if the increased DMNTs mRNA in lymphocytes after cannabis ingestion is also reflected in the brain, these effects could be one factor contributing to the effects of cannabis on provoking schizophrenic symptoms in individuals with increased genetic or environmental vulnerabilities to developing this illness. The higher methylation reported for MAPT and NRXN1 after THC consumption was also interpreted as possibly disadvantageous in schizophrenia, as higher methylation generally leads to reduced readability of genes, which might further impair reduced synaptic connections ( 8 ).…”

“…In this study, CB1 mRNA was decreased in THC-dependent smokers accompanied by a higher CB1 promoter methylation associated with the reduced amount of CBR1 mRNA, whereas CB2 mRNA was not different ( 7 ). Methylation rates in two synapse genes [microtubule-associated-protein Tau (MAPT) and neurexin (NRXN1)] measured in blood were lower in non-THC-consumer schizophrenics but increased with consumption of THC ( 8 ). Inflammatory disturbances are also evident with chronic psychotic disorders and CB2 receptors are expressed on immune cells.…”

Methylomic alteration in peripheral blood lymphocytes of prodromal stage and first-episode Chinese Han schizophrenia patients

“…We then asked the possible association between domains of MCCB and abnormal DNA methylation. In the PRS group of discovery cohort, we detected significant correlations between MCCB performance and the methylation level of probes in 8,38,43,44 and miRNA interference study (SHANK2, SYT1, C10orf26, and CALN1) [45][46][47][48] . These shared loci may presumably promote the development and phase transition of schizophrenia.…”

“…These changes are often retained after mitosis and some can be inherited across generations 5 . Epigenetic changes are prominent in cancer 6 and have been reported in depression and schizophrenia 7,8 .…”