Adolescent Δ9-Tetrahydrocannabinol Exposure and Astrocyte-Specific Genetic Vulnerability Converge on Nuclear Factor-κB-Cyclooxygenase-2 Signaling to Impair Memory in Adulthood.
Yan Jouroukhin, Xiaolei Zhu, Alexey V Shevelkin, Yuto Hasegawa, Bagrat Abazyan, Atsushi Saito, Jonathan Pevsner, Atsushi Kamiya, Mikhail V Pletnikov
Biological Psychiatry August 16, 2018 DOI: 10.1016/j.biopsych.2018.07.024 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Mice with inducible astrocyte-specific expression of dominant-negative DISC1 or astrocytic Disc1 knockdown, exposed to Δ9-THC during adolescence |
| Interventions | Δ9-tetrahydrocannabinol (Δ9-THC) NS398 |
| Topics | Cannabis |
| Keywords | Hippocampus Pyramidal cells Astrocytes Presynaptic terminals Animals Mice, transgenic Sulfonamides Nitrobenzenes Parvalbumins Nf-kappa b Nerve tissue proteins Memory Age factors Signal transduction Female Cyclooxygenase 2 Gene knockdown techniques Ca3 region, hippocampal Dronabinol Recognition, psychology Adolescence Cognitive dysfunction Gene-environment interaction |
| Key findings | Astrocyte-specific expression of dominant-negative DISC1 and adolescent Δ9-THC treatment synergistically impaired recognition memory in adult mice, an effect also seen with astrocytic Disc1 knockdown. The cognitive deficits were accompanied by activation of the NF-κB-cyclooxygenase-2 pathway in astrocytes and loss of parvalbumin-positive inhibitory boutons in hippocampal CA3, and were prevented by adolescent treatment with the COX-2 inhibitor NS398. |
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.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 4
- Chronic adolescent exposure to cannabis in mice leads to sex-biased changes in gene expression networks across brain regions Neuropsychopharmacology August 22, 2022
- THC and CBD: Similarities and differences between siblings. Neuron February 1, 2023
- The independent and combined effects of cannabis use and systemic inflammation during the early stages of psychosis: exploring the two-hit hypothesis. Psychological Medicine December 1, 2022
- Phytocannabinoids and schizophrenia: Focus on adolescence as a critical window of enhanced vulnerability and opportunity for treatment. Pharmacological Research December 1, 2021
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