Astroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons. (15th May 2019)

• Record Type: Journal Article
• Authors: Ruiz-Calvo, Andrea; Bajo-Grañeras, Raquel; Maroto, Irene B.; Zian, Debora; Grabner, Gernot F.; García-Taboada, Elena; Resel, Eva; Zechner, Rudolf; Zimmermann, Robert; Ortega-Gutiérrez, Silvia; Galve-Roperh, Ismael; Bellocchio, Luigi; Guzmán, Manuel
• Is Part Of: Neuropharmacology. Volume 150(2019)
• Page Start: 134
• Page End: 144
• Publication Date: 2019-05-15
• Subjects: Endocannabinoid -- Monoacylglycerol lipase -- Cannabinoid receptor -- Astrocyte -- Medium spiny neuron -- Neuroprotection; 2-AG 2-arachidonoylglycerol -- CFP cyan fluorescent protein -- DARPP-32 dopamine- and cAMP-regulated phosphoprotein of 32 kDa -- GFAP glial fibrillary acidic protein -- HD Huntington's disease -- MGL monoacylglycerol lipase -- MSN medium spiny neuron -- PSD-95 post-synaptic density protein 95 -- PEA palmitoylethanolamide -- rAAV recombinant adeno-associated virus -- THC Δ9-tetrahydrocannabinol -- TNFα tumor necrosis factor-α; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.03.027
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Cannabinoids exert neuroprotection in a wide array of preclinical models. A number of these studies has focused on cannabinoid CB1 receptors in striatal medium spiny neurons (MSNs) and the most characteristic MSN-degenerative disease, Huntington's disease (HD). Accruing evidence supports that astrocytes contribute to drive HD progression, and that they express CB1 receptors, degrade endocannabinoids, and modulate endocannabinergic transmission. However, the possible role of the astroglial endocannabinoid system in controlling MSN integrity remains unknown. Here, we show that JZL-184, a selective inhibitor of monoacylglycerol lipase (MGL), the key enzyme that deactivates the endocannabinoid 2-arachidonoylglycerol, prevented the mutant huntingtin-induced up-regulation of the pro-inflammatory cytokine tumor necrosis factor-α in primary mouse striatal astrocytes via CB1 receptors. To study the role of astroglial MGL in vivo, we injected stereotactically into the mouse dorsal striatum viral vectors that encode mutant or normal huntingtin under the control of the glial fibrillary acidic protein promoter. We observed that, in wild-type mice, pharmacological blockade of MGL with JZL-184 (8 mg/kg/day, i.p.) conferred neuroprotection against mutant huntingtin-induced striatal damage, as evidenced by the prevention of MSN loss, astrogliosis, and motor coordination impairment. We next found that conditional mutant mice bearing a genetic deletion of MGL selectively in astroglial cells (MGL floxed/floxed;GFAP-Cre/+ mice) were resistant to mutant huntingtin-induced MSN loss, astrogliosis, and motor coordination impairment. Taken together, these data support that astroglial MGL controls the availability of a 2-arachidonoylglycerol pool that ensues protection of MSNs in the mouse striatum in vivo, thus providing a potential druggable target for reducing striatal neurodegeneration. Graphical abstract: Image 1 Highlights: The role of the astroglial endocannabinoid system in neuroprotection is unknown. Expression of mutant huntingtin in striatal astrocytes damages striatal neurons. Pharmacological blockade of MGL protects striatal neurons from damage. Genetic inactivation of astroglial MGL protects striatal neurons from damage. Astroglial MGL determines a neuroprotective endocannabinoid pool in the striatum.