Restoration of CB1 receptor function in hippocampal GABAergic neurons rescues memory deficits in Huntington's disease models
Por:
Di Franco, N, de Tena, IB, Sanchez-Ruiz, A, Pereda-Velarde, A, Enfedaque, F, Gónzalez-Arias, C, Rio, LMM, Bortolozzi, A, Rodriguez-Puertas, R, Costas-Insua, C, Molina-Porcel, L, Vazquez-Oliver, A, Ozaita, A, Guzmán, M, Perea, G, Ginés, S
Publicada:
25 ago 2025
Resumen:
BackgroundDysregulation of the endocannabinoid system (eCBS) and the loss of CB1 receptors (CB1R) in the basal ganglia are well-established hallmarks of Huntington's disease (HD). As a result, significant research efforts have focused on targeting the eCBS to alleviate motor disturbances associated with the disease. Beyond its role in motor control, the eCBS is a complex signaling network critically involved in regulating learning and memory. Despite this, the potential involvement of eCBS dysfunction in the cognitive decline characteristic of HD, often manifested well before motor dysfunction, has remained largely unexplored.MethodsCB1R expression in the hippocampus was evaluated in both human HD samples and HD mouse models (R6/1 and HdhQ7/Q111 models, including both sexes) using Western blotting, immunohistochemistry, and radioligand binding assays. To restore CB1R function, CB1R agonist WIN-55212-2 was systemically administered, or viral vectors encoding CB1R were locally infused into the hippocampus of HD mice. A multidisciplinary approach combining behavioral, biochemical, electrophysiological, and morphological analyses, was employed to investigate the molecular mechanisms underlying the effects of CB1R activation in the context of HD-related cognitive dysfunction.ResultsIn both human HD samples and HD mouse models, CB1R protein levels were reduced in the hippocampus, accompanied by structural synaptic alterations and impairment in spatial, recognition and working memory. Moreover, hippocampal depolarization-induced suppression of inhibition was significantly disrupted in R6/1 mice. Administration of WIN-55212-2 successfully restored these synaptic and cognitive deficits. Immunohistochemical analysis revealed that the CB1R decrease was specifically localized to GABAergic interneurons within the hippocampus. Notably, targeted restoration of CB1R expression in these interneurons via viral vector delivery was sufficient to rescue hippocampal-dependent memory deficits in HD mice.ConclusionThis study suggests that impaired CB1R function in hippocampal GABAergic interneurons contributes to memory dysfunction in HD.
Filiaciones:
Di Franco, N:
Univ Barcelona, Inst Neurociencies, Dept Biomed, Fac Med & Ciencies Salut, Barcelona, Spain
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Sobre Enfermedades Neurodege, Madrid, Spain
de Tena, IB:
Univ Basque Country UPV EHU, Fac Med & Nursing, Dept Pharmacol, Leioa, Spain
Biocruces Bizkaia Hlth Res Inst, Neurodegenerat Dis, Baracaldo, Spain
Sanchez-Ruiz, A:
CSIC, Inst Cajal, Madrid, Spain
Pereda-Velarde, A:
Univ Barcelona, Inst Neurociencies, Dept Biomed, Fac Med & Ciencies Salut, Barcelona, Spain
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Sobre Enfermedades Neurodege, Madrid, Spain
Enfedaque, F:
Univ Barcelona, Inst Neurociencies, Dept Biomed, Fac Med & Ciencies Salut, Barcelona, Spain
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Sobre Enfermedades Neurodege, Madrid, Spain
Gónzalez-Arias, C:
CSIC, Inst Cajal, Madrid, Spain
Rio, LMM:
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona, Spain
CSIC, Inst Invest Biomed Barcelona, Dept Neurochem & Neuropharmacol, IIBB, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain
Bortolozzi, A:
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona, Spain
CSIC, Inst Invest Biomed Barcelona, Dept Neurochem & Neuropharmacol, IIBB, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain
Rodriguez-Puertas, R:
Univ Basque Country UPV EHU, Fac Med & Nursing, Dept Pharmacol, Leioa, Spain
Biocruces Bizkaia Hlth Res Inst, Neurodegenerat Dis, Baracaldo, Spain
Costas-Insua, C:
Inst Salud Carlos III, Ctr Invest Biomed Red Sobre Enfermedades Neurodege, Madrid, Spain
Univ Complutense, Inst Univ Invest Neuroquim IUIN, Madrid, Spain
Inst Ramon & Cajal Invest Sanitaria IRYCIS, Madrid, Spain
Univ Heidelberg ZMBH, Ctr Mol Biol, Heidelberg, Germany
Molina-Porcel, L:
Univ Barcelona, Inst Invest Biomed August Pi i Sunyer IDIBAPS, Alzheimers Dis & Other Cognit Disorders Unit, Neurol Serv,Hosp Clin,I Fundacio Recerca Clin Barc, Barcelona, Spain
IDIBAPS, Biobanc Hosp Clin, Neurol Tissue Bank, FRCB, Barcelona, Spain
Vazquez-Oliver, A:
Inst Salud Carlos III, Ctr Invest Biomed Red Sobre Enfermedades Neurodege, Madrid, Spain
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB, Neurol Dept, Movement Disorders Unit, Barcelona 08041, Spain
Ozaita, A:
Univ Pompeu Fabra, Dept Med & Life Sci, Barcelona, Spain
Guzmán, M:
Inst Salud Carlos III, Ctr Invest Biomed Red Sobre Enfermedades Neurodege, Madrid, Spain
Univ Complutense, Inst Univ Invest Neuroquim IUIN, Madrid, Spain
Inst Ramon & Cajal Invest Sanitaria IRYCIS, Madrid, Spain
Perea, G:
CSIC, Inst Cajal, Madrid, Spain
Ginés, S:
Univ Barcelona, Inst Neurociencies, Dept Biomed, Fac Med & Ciencies Salut, Barcelona, Spain
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Sobre Enfermedades Neurodege, Madrid, Spain
Green Accepted, Green Submitted, gold
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