Abstract
Background
Cannabis remains one of the most widely abused drugs during pregnancy. In utero exposure
to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC), can result in long-term neuropsychiatric risk for the
progeny. This study investigated epigenetic signatures underlying these enduring consequences.
Methods
Rat dams were exposed daily to THC (0.15 mg/kg) during pregnancy, and adult male offspring
were examined for reward and depressive-like behavioral endophenotypes. Using unbiased
sequencing approaches, we explored transcriptional and epigenetic profiles in the
nucleus accumbens (NAc), a brain area central to reward and emotional processing.
An in vitro CRISPR (clustered regularly interspaced short palindromic repeats) activation
model coupled with RNA sequencing was also applied to study specific consequences
of epigenetic dysregulation, and altered molecular signatures were compared with human
major depressive disorder transcriptome datasets.
Results
Prenatal THC exposure induced increased motivation for food, heightened learned helplessness
and anhedonia, and altered stress sensitivity. We identified a robust increase specific
to males in the expression of Kmt2a (histone-lysine N-methyltransferase 2A) that targets H3K4 (lysine 4 on histone H3) in cellular chromatin.
Normalizing Kmt2a in the NAc rescued the motivational phenotype of prenatally THC-exposed animals.
Comparison of RNA- and H3K4me3-sequencing datasets from the NAc of rat offspring with
the in vitro model of Kmt2a upregulation revealed overlapping, significant disturbances in pathways that mediate
synaptic plasticity. Similar transcriptional alterations were detected in human major
depressive disorder.
Conclusions
These studies provide direct evidence for the persistent effects of prenatal cannabis
exposure on transcriptional and epigenetic deviations in the NAc via Kmt2a dysregulation and associated psychiatric vulnerability.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Prevalence and patterns of marijuana use among pregnant and nonpregnant women of reproductive age.Am J Obstet Gynecol. 2015; 213: 201.e1-201.e10
- Self-reported medical and nonmedical cannabis use among pregnant women in the United States.JAMA. 2019; 322: 167-169
- Self-reported daily, weekly, and monthly cannabis use among women before and during pregnancy.JAMA Netw Open. 2019; 2e196471
- Reprint of: Survey of medicinal cannabis use among childbearing women: Patterns of its use in pregnancy and retroactive self-assessment of its efficacy against ‘morning sickness.Complement Ther Clin Pract. 2009; 15: 242-246
- Marijuana use and maternal experiences of severe nausea during pregnancy in Hawai’i.Hawaii J Med Public Health. 2014; 73: 283-287
- Human placental transfer of cannabinoids.N Engl J Med. 1984; 311: 797
- Penetration of delta-9-tetrahydrocannabinol and 11-OH-delta-9-tetrahydrocannabinol through the blood-brain barrier.Acta Pharmacol Toxicol (Copenh). 1977; 41: 33-38
- The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin.Br J Pharmacol. 2008; 153: 199-215
- Publication trends for alcohol, tobacco, and narcotics in MEDLARS.Ann N Y Acad Sci. 1986; 477: 103-104
- Prenatal marijuana exposure: Effect on child depressive symptoms at ten years of age.Neurotoxicol Teratol. 2005; 27: 439-448
- Predictors and correlates of high levels of depression and anxiety symptoms among children at age 10.J Am Acad Child Adolesc Psychiatry. 2006; 45: 223-230
- Effects of prenatal cigarette and marijuana exposure on drug use among offspring.Neurotoxicol Teratol. 2005; 27: 267-277
- School achievement in 14-year-old youths prenatally exposed to marijuana.Neurotoxicol Teratol. 2012; 34: 161-167
- The Generation R Study: Design and cohort update 2017.Eur J Epidemiol. 2016; 31: 1243-1264
- Prenatal exposures to tobacco and cannabis: Associations with adult electronic cigarette use.Drug Alcohol Depend. 2018; 188: 209-215
- Adolescent initiation of licit and illicit substance use: Impact of intrauterine exposures and post-natal exposure to violence.Neurotoxicol Teratol. 2011; 33: 100-109
- Young children who commit crime: Epidemiology, developmental origins, risk factors, early interventions, and policy implications.Dev Psychopathol. 2000; 12: 737-762
- The link between mother and adolescent substance use: Intergenerational findings from the British cohort study.Longit Life Course Stud. 2014; 5: 56-63
- Childhood conduct disorder trajectories, prior risk factors and cannabis use at age 16: Birth cohort study.Addiction. 2013; 108: 2129-2138
- Update on the developmental consequences of cannabis use during pregnancy and lactation.Birth Defects Res. 2020; 112: 1126-1138
- Neurobiological consequences of maternal cannabis on human fetal development and its neuropsychiatric outcome.Eur Arch Psychiatry Clin Neurosci. 2009; 259: 395-412
- Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment.Eur J Neurosci. 2011; 34: 1574-1583
- The cannabinoid receptors.Prostaglandins Other Lipid Mediat. 2002; 68–69: 619-631
- Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation.Prog Lipid Res. 2013; 52: 633-650
- Type-1 (CB1) cannabinoid receptor promotes neuronal differentiation and maturation of neural stem cells.PLOS ONE. 2013; 8e54271
- Molecular model of cannabis sensitivity in developing neuronal circuits.Trends Pharmacol Sci. 2011; 32: 551-561
- Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway.EMBO J. 2014; 33: 668-685
- Cannabis and synaptic reprogramming of the developing brain.Nat Rev Neurosci. 2021; 22: 423-438
- Neural systems of reinforcement for drug addiction: From actions to habits to compulsion.Nat Neurosci. 2005; 8: 1481-1489
- Integrating neurotransmission in striatal medium spiny neurons.Adv Exp Med Biol. 2012; 970: 407-429
- Neurocircuitry of addiction.Neuropsychopharmacology. 2010; 35: 217-238
- Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory.J Neurosci. 2015; 35: 5097-5108
- Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat.Neurotoxicology. 1993; 14: 83-144
- The GABAB receptor agonists baclofen and CGP44532 decreased nicotine self-administration in the rat.Psychopharmacol (Berl). 2004; 172: 179-186
- Effects of increment size and reinforcer volume on progressive ratio performance.J Exp Anal Behav. 1963; 6: 387-392
- Using the rat forced swim test to assess antidepressant-like activity in rodents.Nat Protoc. 2012; 7: 1009-1014
- HDAC3 is a critical negative regulator of long-term memory formation.J Neurosci. 2011; 31: 764-774
- Methamphetamine-associated memory is regulated by a writer and an eraser of permissive histone methylation.Biol Psychiatry. 2014; 76: 57-65
- MicroRNA-182 regulates amygdala-dependent memory formation.J Neurosci. 2013; 33: 1734-1740
- GOrilla: A tool for discovery and visualization of enriched GO terms in ranked gene lists.BMC Bioinformatics. 2009; 10: 48
- STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets.Nucleic Acids Res. 2019; 47: D607-D613
- Computing topological parameters of biological networks.Bioinformatics. 2008; 24: 282-284
- Cytoscape: A software environment for integrated models of biomolecular interaction networks.Genome Res. 2003; 13: 2498-2504
- DGCA: A comprehensive R package for Differential Gene Correlation Analysis.BMC Syst Biol. 2016; 10: 106
- Transcriptome alterations in prefrontal pyramidal cells distinguish schizophrenia from bipolar and major depressive disorders.Biol Psychiatry. 2017; 82: 594-600
- Sex-specific transcriptional signatures in human depression.Nat Med. 2017; 23: 1102-1111
- Prenatal cannabis exposure increases heroin seeking with allostatic changes in limbic enkephalin systems in adulthood.Biol Psychiatry. 2007; 61: 554-563
- Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring.Biol Psychiatry. 2011; 70: 763-769
- Behavioural despair in rats: A new model sensitive to antidepressant treatments.Eur J Pharmacol. 1978; 47: 379-391
- “Behavioural despair” in rats and mice: strain differences and the effects of imipramine.Eur J Pharmacol. 1978; 51: 291-294
- The cancer COMPASS: Navigating the functions of MLL complexes in cancer.Cancer Genet. 2015; 208: 178-191
- Mixed lineage leukemia: A structure-function perspective of the MLL1 protein.FEBS Journal. 2010; 277: 1832-1842
- The many facets of MLL1 regulation.Biopolymers. 2013; 99: 136-145
- The epigenetic factor Kmt2a/Mll1 regulates neural progenitor proliferation and neuronal and glial differentiation.Dev Neurobiol. 2015; 75: 452-462
- Epigenetic regulation in human brain-focus on histone lysine methylation.Biol Psychiatry. 2009; 65: 198-203
- Paternal THC exposure in rats causes long-lasting neurobehavioral effects in the offspring.Neurotoxicol Teratol. 2019; 74: 106806
- Prenatal tetrahydrocannabinol (THC) alters cognitive function and amphetamine response from weaning to adulthood in the rat.Neurotoxicol Teratol. 2012; 34: 63-71
- Parental THC exposure leads to compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent generation.Neuropsychopharmacology. 2014; 39: 1315-1323
- 36- and 48-month neurobehavioral follow-up of children prenatally exposed to marijuana, cigarettes, and alcohol.J Dev Behav Pediatr. 1990; 11: 49-58
- The effects of prenatal marijuana exposure on delinquent behaviors are mediated by measures of neurocognitive functioning.Neurotoxicol Teratol. 2011; 33: 129-136
- The health consequences of smoking--50 years of progress: a report of the surgeon general. Public Health Service, Office of the Surgeon General.United States Department of Health and Human Services, Public Health Service, Office of the Surgeon General, Rockville, MD2014
- Prenatal cannabis exposure—The “first hit” to the endocannabinoid system.Neurotoxicol Teratol. 2016; 58: 5-14
- KMT2A and KMT2B mediate memory function by affecting distinct genomic regions.Cell Rep. 2017; 20: 538-548
- Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals.Neuron. 2001; 29: 729-738
- Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses.Nature. 2001; 410: 588-592
- Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons.Mol Pharmacol. 2004; 65: 665-674
- Endocannabinoid 2-arachidonoylglycerol suppresses LPS-induced inhibition of A-type potassium channel currents in caudate nucleus neurons through CB1 receptor.J Mol Neurosci. 2016; 59: 493-503
- Promoter decommissioning by the NuRD chromatin remodeling complex triggers synaptic connectivity in the mammalian brain.Neuron. 2014; 83: 122-134
- CREB family transcription factors are major mediators of BDNF transcriptional autoregulation in cortical neurons.J Neurosci. 2020; 40: 1405-1426
- New friends for Ago2 in neuronal plasticity.EMBO J. 2015; 34: 2213-2214
Article Info
Publication History
Published online: September 27, 2021
Accepted:
September 14,
2021
Received in revised form:
September 14,
2021
Received:
February 18,
2021
Footnotes
CAV is currently affiliated with Georgia State University, Atlanta, Georgia.
Identification
Copyright
© 2021 Society of Biological Psychiatry.