Adolescent Δ
| Autor: | Yan, Jouroukhin, Xiaolei, Zhu, Alexey V, Shevelkin, Yuto, Hasegawa, Bagrat, Abazyan, Atsushi, Saito, Jonathan, Pevsner, Atsushi, Kamiya, Mikhail V, Pletnikov |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Sulfonamides Pyramidal Cells Age Factors NF-kappa B Presynaptic Terminals Mice Transgenic Nerve Tissue Proteins Recognition Psychology CA3 Region Hippocampal Hippocampus Article Mice Parvalbumins Cyclooxygenase 2 Memory Astrocytes Gene Knockdown Techniques mental disorders Animals Female Dronabinol Nitrobenzenes Signal Transduction |
| Zdroj: | Biol Psychiatry |
| ISSN: | 1873-2402 |
| Popis: | BACKGROUND: Although several studies linked adolescent cannabis use to long-term cognitive dysfunction, there are negative reports too. The fact that not all users develop cognitive impairment suggests a genetic vulnerability to adverse effects of cannabis, which are attributed to action of delta-9-tetrahydrocannabinol (Δ(9)-THC), a cannabis constituent and partial agonist of brain cannabinoid receptor 1 (CNR1). As both neurons and glial cells express CNR1, genetic vulnerability could influence Δ(9)-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 Δ(9)-THC exposure to impair recognition memory in adulthood. RESULTS: Selective expression of DN-DISC1 in astrocytes and adolescent treatment with Δ(9)-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 Δ(9)-THC during adolescence. At the molecular level, DN-DISC1 and Δ(9)-THC synergistically activated the NF-kB-COX-2 pathway in astrocytes and decreased immunoreactivity of parvalbumin-positive pre-synaptic inhibitory boutons around pyramidal neurons of the hippocampal CA3 area. The cognitive abnormalities were prevented in DN-DISC1 mice exposed to Δ(9)-THC by simultaneous adolescent treatment with the COX-2 inhibitor, NS389. 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 Δ(9)-THC-produced cognitive impairments via convergent inflammatory signaling, suggesting possible targets for preventing adverse effects of cannabis within susceptible individuals. |
| Databáze: | OpenAIRE |
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