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

Biol Psychiatry. 2019 Jun 1;85(11):891-903. doi: 10.1016/j.biopsych.2018.07.024. Epub 2018 Aug 16.

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.

Keywords: Adolescence; Astrocytes; Cannabis; Cognitive dysfunction; Gene-environment interaction; Hippocampus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Astrocytes / metabolism
  • CA3 Region, Hippocampal / immunology
  • Cyclooxygenase 2 / metabolism*
  • Dronabinol / adverse effects*
  • Female
  • Gene Knockdown Techniques
  • Hippocampus / metabolism
  • Male
  • Memory / drug effects*
  • Mice
  • Mice, Transgenic
  • NF-kappa B / metabolism*
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics*
  • Nitrobenzenes / pharmacology
  • Parvalbumins / metabolism
  • Presynaptic Terminals / drug effects
  • Pyramidal Cells / immunology
  • Recognition, Psychology / drug effects*
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology

Substances

  • Disc1 protein, mouse
  • NF-kappa B
  • Nerve Tissue Proteins
  • Nitrobenzenes
  • Parvalbumins
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Dronabinol
  • Cyclooxygenase 2