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Altered brain cannabinoid 1 receptor mRNA expression across postnatal development in the MAM model of schizophrenia.

ABSTRACT: Altered cannabinoid 1 receptor (CB1R) expression has been reported in the brain of subjects with schizophrenia, a developmental mental illness that usually emerges in late adolescence/early adulthood. However, the developmental period at which changes in the CB1R expression appear in schizophrenia is unknown. To gain insight into this factor, we assessed the postnatal developmental trajectory of CB1R expression in the methylazoxymethanol (MAM) model of schizophrenia. Using in situ hybridization with film and grain analyses, CB1R messenger RNA (mRNA) levels were quantified in multiple brain regions, including the medial prefrontal cortex (mPFC), secondary motor cortex, dorsomedial and dorsolateral striatum, dorsal subregions and ventral subiculum of the hippocampus, of MAM-treated rats and normal controls at three developmental periods [juvenile - postnatal day (PD) 30; adolescence - PD45; and adulthood - PD85]. In all brain regions studied, CB1R mRNA levels were highest in juveniles and then decreased progressively toward adolescent and adult levels in control and MAM-treated rats. However, in MAM-treated rats, CB1R mRNA levels were lower in the mPFC at PD85 and higher in the dorsolateral striatum at PD45 and PD85 relative to controls. Cellular analyses confirmed the changes in CB1R mRNA expression in MAM-treated rats. These findings are in accordance with previous studies showing a decrease in the CB1R mRNA expression from juvenile period to adolescence to adulthood in cortical, striatal, and hippocampal regions. Additionally, similar to most of the schizophrenia-like signs observed in the MAM model, embryonic exposure to MAM leads to schizophrenia-related changes in CB1R mRNA expression that only emerge later in development.

SUBMITTER: Gomes FV

PROVIDER: S-EPMC6203675 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Altered brain cannabinoid 1 receptor mRNA expression across postnatal development in the MAM model of schizophrenia.

Gomes Felipe V FV Edelson Jessica R JR Volk David W DW Grace Anthony A AA

Schizophrenia research 20180426

Altered cannabinoid 1 receptor (CB1R) expression has been reported in the brain of subjects with schizophrenia, a developmental mental illness that usually emerges in late adolescence/early adulthood. However, the developmental period at which changes in the CB1R expression appear in schizophrenia is unknown. To gain insight into this factor, we assessed the postnatal developmental trajectory of CB1R expression in the methylazoxymethanol (MAM) model of schizophrenia. Using in situ hybridization ...[more]

PMID: 29705007

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Project description:Beyond being one the most widely used psychoactive drugs in the world, cannabis has been identified as an environmental risk factor for psychosis. Though the relationship between cannabis use and psychiatric disorders remains controversial, consistent association between early adolescent cannabis use and the subsequent risk of psychosis suggested adolescence may be a particularly vulnerable period. Previous findings on gene by environment interactions indicated that cannabis use may only increase the risk for psychosis in the subjects who have a specific genetic vulnerability. The type 1 cannabinoid receptor (CB1), encoded by the CNR1 gene, is a key component of the endocannabinoid system. As the primary endocannabinoid receptor in the brain, CB1 is the main molecular target of the endocannabinoid ligand, as well as tetrahydrocannabinol (THC), the principal psychoactive ingredient of cannabis. In this study, we have examined mRNA expression and DNA methylation of CNR1 in human prefrontal cortex (PFC), hippocampus, and caudate samples. The expression of CNR1 is higher in fetal PFC and hippocampus, then drops down dramatically after birth. The lifespan trajectory of CNR1 expression in the DLPFC differentially correlated with age by allelic variation at rs4680, a functional polymorphism in the COMT gene. Compared with COMT methionine158 carriers, Caucasian carriers of the COMT valine158 allele have a stronger negative correlation between the expression of CNR1 in DLPFC and age. In contrast, the methylation level of cg02498983, which is negatively correlated with the expression of CNR1 in PFC, showed the strongest positive correlation with age in PFC of Caucasian carriers of COMT valine158. Additionally, we have observed decreased mRNA expression of CNR1 in the DLPFC of patients with schizophrenia. Further analysis revealed a positive eQTL SNP, rs806368, which predicted the expression of a novel transcript of CNR1 in human DLPFC, hippocampus and caudate. This SNP has been associated with addiction and other psychiatric disorders. THC or ethanol are each significantly associated with dysregulated expression of CNR1 in the PFC of patients with affective disorder, and the expression of CNR1 is significantly upregulated in the PFC of schizophrenia patients who completed suicide. Our results support previous studies that have implicated the endocannabinoid system in the pathology of schizophrenia and provided additional insight into the mechanism of increasing risk for schizophrenia in the adolescent cannabis users.

Project description:Schizophrenia is highly heritable and aggregating in families, but genetics alone does not exclusively explain the pathogenesis. Many risk factors, including childhood trauma, viral infections, migration, and the use of cannabis, are associated with schizophrenia. Adolescence seems to be the critical period where symptoms of the disease manifest. This work focuses on studying an epigenetic regulatory mechanism (the role of DNA methylation) and its interaction with mRNA expression during development, with a particular emphasis on adolescence. The presumptions regarding the role of aberrant neurodevelopment in schizophrenia were tested in the Methyl-Azoxy-Methanol (MAM) animal model. MAM treatment induces neurodevelopmental disruptions and behavioral deficits in off-springs of the treated animals reminiscent of those observed in schizophrenia and is thus considered a promising model for studying this pathology. On a gestational day-17, adult pregnant rats were treated with the antimitotic agent MAM. Experimental animals were divided into groups and subgroups according to substance treatment (MAM and vehicle agent [Sham]) and age of analysis (pre-adolescent and post-adolescent). Methylation and mRNA expression analysis of four candidate genes, which are often implicated in schizophrenia, with special emphasis on the Dopamine hypothesis i.e., Dopamine receptor D2 (Drd2), and the "co-factors" Disrupted in schizophrenia 1 (DISC1), Synaptophysin (Syp), and Dystrobrevin-binding protein 1 (Dtnbp1), was performed in the Gyrus cingulum (CING) and prefrontal cortex (PFC). Data were analyzed to observe the effect of substance treatment between groups and the impact of adolescence within-group. We found reduced pre-adolescent expression levels of Drd2 in both brain areas under the application of MAM. The "co-factor genes" did not show high deviations in mRNA expression levels but high alterations of methylation rates under the application of MAM (up to ~20%), which diminished in the further time course, reaching a comparable level like in Sham control animals after adolescence. The pre-adolescent reduction in DRD2 expression might be interpreted as downregulation of the receptor due to hyperdopaminergic signaling from the ventral tegmental area (VTA), eventually even to both investigated brain regions. The notable alterations of methylation rates in the three analyzed co-factor genes might be interpreted as attempt to compensate for the altered dopaminergic neurotransmission.

Dataset Information

Altered brain cannabinoid 1 receptor mRNA expression across postnatal development in the MAM model of schizophrenia.

Publications

Altered brain cannabinoid 1 receptor mRNA expression across postnatal development in the MAM model of schizophrenia.

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