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Biol Psychiatry. 2018 Aug 16. pii: S0006-3223(18)31746-3. doi: 10.1016/j.biopsych.2018.07.024. [Epub ahead of print]

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

Author information

1
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
2
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland; Kennedy Krieger Institute, Baltimore, Maryland.
3
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: akamiya1@jhmi.edu.
4
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: mpletni1@jhu.edu.

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

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