Adolescent Δ9-Tetrahydrocannabinol Exposure and Astrocyte-Specific Genetic Vulnerability Converge on Nuclear Factor-κB–Cyclooxygenase-2 Signaling to Impair Memory in Adulthood

Yan Jouroukhin, Xiaolei Zhu, Alexey V. Shevelkin, Yuto Hasegawa, Bagrat Abazyan, Atsushi Saito, Jonathan Pevsner, Atsushi Kamiya, Mikhail V. Pletnikov

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Although several studies have linked adolescent cannabis use to long-term cognitive dysfunction, there are negative reports as well. The fact that not all users develop cognitive impairment suggests a genetic vulnerability to adverse effects of cannabis, which are attributed to action of Δ9-tetrahydrocannabinol (Δ9-THC), a cannabis constituent and partial agonist of brain cannabinoid receptor 1. As both neurons and glial cells express cannabinoid receptor 1, genetic vulnerability could influence Δ9-THC–induced signaling in a cell type–specific manner. Methods: Here we use an animal model of inducible expression of dominant-negative disrupted in schizophrenia 1 (DN-DISC1)selectively in astrocytes to evaluate the molecular mechanisms, whereby an astrocyte genetic vulnerability could interact with adolescent Δ9-THC exposure to impair recognition memory in adulthood. Results: Selective expression of DN-DISC1 in astrocytes and adolescent treatment with Δ9-THC synergistically affected recognition memory in adult mice. Similar deficits in recognition memory were observed following knockdown of endogenous Disc1 in hippocampal astrocytes in mice treated with Δ9-THC during adolescence. At the molecular level, DN-DISC1 and Δ9-THC synergistically activated the nuclear factor-κB–cyclooxygenase-2 pathway in astrocytes and decreased immunoreactivity of parvalbumin-positive presynaptic inhibitory boutons around pyramidal neurons of the hippocampal CA3 area. The cognitive abnormalities were prevented in DN-DISC1 mice exposed to Δ9-THC by simultaneous adolescent treatment with the cyclooxygenase-2 inhibitor, NS398. Conclusions: Our data demonstrate that individual vulnerability to cannabis can be exclusively mediated by astrocytes. Results of this work suggest that genetic predisposition within astrocytes can exaggerate Δ9-THC–produced cognitive impairments via convergent inflammatory signaling, suggesting possible targets for preventing adverse effects of cannabis within susceptible individuals.

Original languageEnglish (US)
Pages (from-to)891-903
Number of pages13
JournalBiological psychiatry
Volume85
Issue number11
DOIs
StatePublished - Jun 1 2019

Keywords

  • Adolescence
  • Astrocytes
  • Cannabis
  • Cognitive dysfunction
  • Gene-environment interaction
  • Hippocampus

ASJC Scopus subject areas

  • Biological Psychiatry

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