title: The CB₁ cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway.
abstract: The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. In particular, the CB1 receptor is highly expressed in the basal ganglia, mostly on terminals of medium-sized spiny neurons, where it plays a key neuromodulatory function. The CB1 receptor also confers neuroprotection in various experimental models of striatal damage. However, the assessment of the physiological relevance and therapeutic potential of the CB1 receptor in basal ganglia-related diseases is hampered, at least in part, by the lack of knowledge of the precise mechanism of CB1 receptor neuroprotective activity. Here, by using an array of pharmacological, genetic and pharmacogenetic (designer receptor exclusively activated by designer drug) approaches, we show that (1) CB1 receptor engagement protects striatal cells from excitotoxic death via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin complex 1 pathway, which, in turn, (2) induces brain-derived neurotrophic factor (BDNF) expression through the selective activation of BDNF gene promoter IV, an effect that is mediated by multiple transcription factors. To assess the possible functional impact of the CB1/BDNF axis in a neurodegenerative-disease context in vivo, we conducted experiments in the R6/2 mouse, a well-established model of Huntington's disease, in which the CB1 receptor and BDNF are known to be severely downregulated in the dorsolateral striatum. Adeno-associated viral vector-enforced re-expression of the CB1 receptor in the dorsolateral striatum of R6/2 mice allowed the re-expression of BDNF and the concerted rescue of the neuropathological deficits in these animals. Collectively, these findings unravel a molecular link between CB1 receptor activation and BDNF expression, and support the relevance of the CB1/BDNF axis in promoting striatal neuron survival.
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.|Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, and the Instituto Universitario de Investigación Neuroquímica (IUIN), Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Blázquez
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.|Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, and the Instituto Universitario de Investigación Neuroquímica (IUIN), Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Chiarlone
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.|Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, and the Instituto Universitario de Investigación Neuroquímica (IUIN), Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Bellocchio
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.|Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, and the Instituto Universitario de Investigación Neuroquímica (IUIN), Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Resel
authors.affiliation: Institute of Gene Technology, Tallinn University of Technology, Tallinn, Estonia.
authors.forename: P
authors.initials: P
authors.lastname: Pruunsild
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.|Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, and the Instituto Universitario de Investigación Neuroquímica (IUIN), Madrid, Spain.
authors.forename: D
authors.initials: D
authors.lastname: García-Rincón
authors.affiliation: Institute of Clinical Neurobiology, University of Würzburg, Würzburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Sendtner
authors.affiliation: Institute of Gene Technology, Tallinn University of Technology, Tallinn, Estonia.
authors.forename: T
authors.initials: T
authors.lastname: Timmusk
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Lutz
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.|Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, and the Instituto Universitario de Investigación Neuroquímica (IUIN), Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Galve-Roperh
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.|Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, and the Instituto Universitario de Investigación Neuroquímica (IUIN), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Guzmán
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003342:Corpus Striatum / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D000066829:Neuroprotection; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019076:Transgenes
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D043884:Receptor, Cannabinoid, CB1; D058570:TOR Serine-Threonine Kinases; C579455:BDNF protein, human