High times for cannabis: Epigenetic imprint and its legacy on brain and behavior

Abstract

Extensive debates continue regarding marijuana (Cannabis spp), the most commonly used illicit substance in many countries worldwide. There has been an exponential increase of cannabis studies over the past two decades but the drug's long-term effects still lack in-depth scientific data. The epigenome is a critical molecular machinery with the capacity to maintain persistent alterations of gene expression and behaviors induced by cannabinoids that have been observed across the individual's lifespan and even into the subsequent generation. Though mechanistic investigations regarding the consequences of developmental cannabis exposure remain sparse, human and animal studies have begun to reveal specific epigenetic disruptions in the brain and the periphery. In this article, we focus attention on long-term disturbances in epigenetic regulation in relation to prenatal, adolescent and parental germline cannabinoid exposure. Expanding knowledge about the protracted molecular memory could help to identify novel targets to develop preventive strategies and treatments for behaviors relevant to neuropsychiatric risks associated with developmental cannabis exposure.

Keywords: Adolescence; Cannabinoid; Chromatin; DNA methylation; Epigenetics; Multigenerational inheritance; Prenatal development; Synaptic plasticity; Transcription.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Cannabis exposure during sensitive periods of development can impact epigenetic mechanisms, leading to persistent gene regulation and behavioral alterations

The two most likely populations to use cannabis are pregnant women and adolescents (indicated by green arrow on top). These developmental phases also correspond to periods when the brain is most vulnerable to the influence of external cannabinoids via interfering with epigenetic mechanisms (shown below the schematic of the developmental cycle). Several epigenetic mechanisms that are relevant to the effects of cannabinoids can interfere with normal gene expression via interacting with DNA elements (e.g. promoters) and transcription factors (proteins that bind to the DNA) to regulate mRNA transcript levels from a gene. Specific regulatory mechanisms include DNA methylation (Me), positioning and post-translational modifications of nucleosomes (small blue balls), recruitment of the transcription complex (sequence-specific and basal transcription factors, RNA polymerase II), and non-coding RNAs. DNA methyltranserases (DNMT) generate 5-methylcytosine (pink stars) at CpG sites. Ten-eleven translocation (TET) proteins mediate the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (green stars), leading to demethylation of the DNA. Modifications of nucleosomal histone tails such as methylation (Me) and acetylation (Ac) are mediated by histone methyltransferases (HMT) and histone acetyltransferases (HAT), respectively. Small RNAs are produced from specific genes and either influence the transcription process or target protein-coding messenger RNAs for degradation. Germ cells (sperm, oocyte) are also sensitive to cannabinoids but the exact underlying epigenetic mechanisms remain to be determined.