title: A preliminary study of endocannabinoid system regulation in psychosis: Distinct alterations of CNR1 promoter DNA methylation in patients with schizophrenia.
abstract: Compelling evidence supports the involvement of the endocannabinoid system (ECS) in psychosis vulnerability. We here evaluated the transcriptional regulation of ECS components in human peripheral blood mononuclear cells (PBMCs) obtained from subjects suffering from bipolar disorder, major depressive disorder and schizophrenia, focusing in particular on the effects of DNA methylation. We observed selective alterations of DNA methylation at the promoter of CNR1, the gene coding for the type-1 cannabinoid receptor, in schizophrenic patients (N=25) with no changes in any other disorder. We confirmed the regulation of CNR1 in a well-validated animal model of schizophrenia, induced by prenatal methylazoxymethanol (MAM) acetate exposure (N=7 per group) where we found, in the prefrontal cortex, a significant increase in CNR1 expression and a consistent reduction in DNA methylation at specific CpG sites of gene promoter. Overall, our findings suggest a selective dysregulation of ECS in psychosis, and highlight the evaluation of CNR1 DNA methylation levels in PBMCs as a potential biomarker for schizophrenia.
authors.affiliation: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Italy; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: cdaddario@unite.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Addario
authors.affiliation: CEITEC/Masaryk University, Brno, Czech Republic; Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Micale
authors.affiliation: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Di Bartolomeo
authors.affiliation: Masaryk University, Faculty of Medicine, Department of Pharmacology, Brno, Czech Republic.
authors.forename: Tibor
authors.initials: T
authors.lastname: Stark
authors.affiliation: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Pucci
authors.affiliation: CEITEC/Masaryk University, Brno, Czech Republic.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sulcova
authors.affiliation: Centro Sant'Ambrogio, Ordine Ospedaliero San Giovanni di Dio-Fatebenefratelli, Cernusco sul Naviglio, Italy.
authors.forename: Mariacarlotta
authors.initials: M
authors.lastname: Palazzo
authors.affiliation: Masaryk University, Faculty of Medicine, Department of Pharmacology, Brno, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Babinska
authors.affiliation: Department of Neuroscience, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cremaschi
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
authors.affiliation: Department of Neuroscience, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Carlo Altamura
authors.affiliation: Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy; European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.affiliation: Department of Neuroscience, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Psychiatry and Behavioral Sciences, Bipolar Disorders Clinic, Stanford University, CA, USA. Electronic address: bernardo.dellosso@unimi.it.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Dell'Osso
mesh_terms: D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008746:Methylazoxymethanol Acetate; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*
chemical_list: C571130:CNR1 protein, human; C543264:Cnr1 protein, rat; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D008746:Methylazoxymethanol Acetate
keywords: Cannabinoid receptor type-1; DNA methylation; Endocannabinoid system (ECS); Methylazoxymethanol (MAM) rat model; Schizophrenia