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

Research output: Contribution to journalArticle

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)
JournalBiological Psychiatry
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Dronabinol
Astrocytes
Cannabis
Schizophrenia
Parvalbumins
Cannabinoid Receptors
Pyramidal Cells
Cyclooxygenase 2 Inhibitors
Genetic Predisposition to Disease
Neuroglia
Animal Models
Neurons
Therapeutics
Recognition (Psychology)
Cognitive Dysfunction

Keywords

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

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

@article{575f42e4e60a45c3a5e050bb81a213e2,
title = "Adolescent Δ9-Tetrahydrocannabinol Exposure and Astrocyte-Specific Genetic Vulnerability Converge on Nuclear Factor-κB–Cyclooxygenase-2 Signaling to Impair Memory in Adulthood",
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",
author = "Yan Jouroukhin and Xiaolei Zhu and Alexey Shevelkin and Yuto Hasegawa and Bagrat Abazyan and Atsushi Saito and Pevsner, {Jonathan A.} and Atsushi Kamiya and Mikhail Pletnikov",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.biopsych.2018.07.024",
language = "English (US)",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",

}

TY - JOUR

T1 - Adolescent Δ9-Tetrahydrocannabinol Exposure and Astrocyte-Specific Genetic Vulnerability Converge on Nuclear Factor-κB–Cyclooxygenase-2 Signaling to Impair Memory in Adulthood

AU - Jouroukhin, Yan

AU - Zhu, Xiaolei

AU - Shevelkin, Alexey

AU - Hasegawa, Yuto

AU - Abazyan, Bagrat

AU - Saito, Atsushi

AU - Pevsner, Jonathan A.

AU - Kamiya, Atsushi

AU - Pletnikov, Mikhail

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Adolescence

KW - Astrocytes

KW - Cannabis

KW - Cognitive dysfunction

KW - Gene-environment interaction

KW - Hippocampus

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U2 - 10.1016/j.biopsych.2018.07.024

DO - 10.1016/j.biopsych.2018.07.024

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SN - 0006-3223

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