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
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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.
