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 V.
AU - Hasegawa, Yuto
AU - Abazyan, Bagrat
AU - Saito, Atsushi
AU - Pevsner, Jonathan
AU - Kamiya, Atsushi
AU - Pletnikov, Mikhail V.
N1 - Funding Information:
This work was supported by National Institute on Drug Abuse Grant No. DA-041208 (to AK, MVP), Conte Center Grant Nos. MH-094268 (to AK, MVP) and MH-083728 (to MVP), and the Brain and Behavior Research Foundation (AK, MVP, AS).
Funding Information:
This work was supported by National Institute on Drug Abuse Grant No. DA-041208 (to AK, MVP), Conte Center Grant Nos. MH-094268 (to AK, MVP)and MH-083728 (to MVP), and the Brain and Behavior Research Foundation (AK, MVP, AS). YJ and BA performed the behavioral experiments, YJ and XZ analyzed the data, XZ and AS performed the biochemical studies, AVS and YH performed morphological experiments, JP supervised RNA sequencing analyses, YJ and MVP wrote the manuscript, and AK and MVP jointly supervised the entire project. We would like to thank Dr. Akira Sawa and Dr. Christopher A. Ross (Johns Hopkins University)for their thoughtful suggestions and comments. We acknowledge Ms. Olga Mychko's expert technical help with immunostaining. We also acknowledge a superb service provided by the Johns Hopkins University Next Generation Sequencing Core. We would like to thank Dr. Sun-Hong Kim (Johns Hopkins University)for his expert assistance with generating adeno-associated viral vectors. We are also grateful to the National Institute on Drug Abuse Drug Supply Program for providing tetrahydrocannabinol. The authors declare no biomedical financial interests or potential conflicts of interest.
Publisher Copyright:
© 2018 Society of Biological Psychiatry
PY - 2019/6/1
Y1 - 2019/6/1
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
M3 - Article
C2 - 30219209
AN - SCOPUS:85053158868
VL - 85
SP - 891
EP - 903
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
IS - 11
ER -