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- Krassnitzer, M, et al.
(författare)
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Resident Astrocytes can Limit Injury to Developing Hippocampal Neurons upon THC Exposure
- 2023
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Ingår i: Neurochemical research. - : Springer Science and Business Media LLC. - 1573-6903 .- 0364-3190. ; 48:4, s. 1242-1253
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Tidskriftsartikel (refereegranskat)abstract
- Cannabis legalization prompted the dilemma if plant-derived recreational drugs can have therapeutic potential and, consequently, how to address their regulation and safe distribution. In parallel, the steady worldwide decriminalization of cannabis and the enhanced content of its main psychoactive compound Δ9-tetrahydrocannabinol (THC), exposes populations to increasing amounts of cannabis and THC across all ages. While adverse effects of cannabis during critical stages of fetal neurodevelopment are investigated, these studies center on neurons alone. Thus, a gap of knowledge exists on how intercellular interactions between neighboring cell types, particularly astrocytes and neurons, could modify THC action. Here, we combine transcriptome analysis, transgenic models, high resolution microscopy and live cell imaging to demonstrate that hippocampal astrocytes accumulate in the strata radiatum and lacunosum moleculare of the CA1 subfield, containing particularly sensitive neurons to stressors, upon long term postnatal THC exposure in vivo. As this altered distribution is not dependent on cell proliferation, we propose that resident astrocytes accumulate in select areas to protect pyramidal neurons and their neurite extensions from pathological damage. Indeed, we could recapitulate the neuroprotective effect of astrocytes in vitro, as their physical presence significantly reduced the death of primary hippocampal neurons upon THC exposure (> 5 µM). Even so, astrocytes are also affected by a reduced metabolic readiness to stressors, as reflected by a downregulation of mitochondrial proteins. Thus, we find that astrocytes exert protective functions on local neurons during THC exposure, even though their mitochondrial electron transport chain is disrupted.
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- Tortoriello, Giuseppe, et al.
(författare)
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Genetic Manipulation of sn-1-Diacylglycerol Lipase and CB1 Cannabinoid Receptor Gain-of-Function Uncover Neuronal 2-Linoleoyl Glycerol Signaling in Drosophila melanogaster
- 2021
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Ingår i: Cannabis and cannabinoid research. - : Mary Ann Liebert. - 2578-5125 .- 2378-8763. ; 6:2, s. 119-136
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: In mammals, sn-1-diacylglycerol lipases (DAGL) generate 2-arachidonoylglycerol (2-AG) that, as the major endocannabinoid, modulates synaptic neurotransmission by acting on CB1 cannabinoid receptors (CB1R). Even though the insect genome codes for inaE, which is a DAGL ortholog (dDAGL), its products and their functions remain unknown particularly because insects lack chordate-type cannabinoid receptors. Materials and Methods: Gain-of-function and loss-of-function genetic manipulations were carried out in Drosophila melanogaster, including the generation of both dDAGL-deficient and mammalian CB1R-overexpressing flies. Neuroanatomy, dietary manipulations coupled with targeted mass spectrometry determination of arachidonic acid and 2-linoleoyl glycerol (2-LG) production, behavioral assays, and signal transduction profiling for Akt and Erk kinases were employed. Findings from Drosophilae were validated by a CB1R-binding assay for 2-LG in mammalian cortical homogenates with functionality confirmed in neurons using high-throughput real-time imaging in vitro. Results: In this study, we show that dDAGL is primarily expressed in the brain and nerve cord of Drosophila during larval development and in adult with 2-LG being its chief product as defined by dietary precursor availability. Overexpression of the human CB1R in the ventral nerve cord compromised the mobility of adult Drosophilae. The causality of 2-LG signaling to CB1R-induced behavioral impairments was shown by inaE inactivation normalizing defunct motor coordination. The 2-LG-induced activation of transgenic CB(1)Rs affected both Akt and Erk kinase cascades by paradoxical signaling. Data from Drosophila models were substantiated by showing 2-LG-mediated displacement of [H-3]CP 55,940 in mouse cortical homogenates and reduced neurite extension and growth cone collapsing responses in cultured mouse neurons. Conclusions: Overall, these results suggest that 2-LG is an endocannabinoid-like signal lipid produced by dDAGL in Drosophila.
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