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00925njm 22002777a 4500 dc Blázquez Ortiz, Cristina author Chiarlone, Anna author Sagredo Ezquioga, Onintza author Aguado Sánchez, Tania author Pazos, Ruth author Resel, Eva author Palazuelos Diego, Javier author Julien, Boris author Salazar, María author Börner, Christine author Benito, Cristina author Carrasco, Carolina author Diez Zaera, María author Paoletti, Paola author Díaz Hernández, Miguel author Ruiz, Carolina author Sendtner, Michael author Lucas, José author García de Yébenes, Justo author Marsicano, Giovanni author Monory, Krisztina author Lutz, Beat author Romero, Julián author Alberch, Jordi author Ginés, Silvia author Kraus, Jürgen author Fernández Ruiz, José Javier author Galve Roperh, Ismael author Guzmán Pastor, Manuel author 2010 Endocannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 cannabinoid receptors. These receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 cannabinoid receptors has been documented in the basal ganglia of patients with Huntington’s disease and animal models. However, the pathophysiological impact of this loss of receptors in Huntington’s disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the cannabinoid Δ9-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the receptors involves the control of the type 1 cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington’s disease. Altogether, these results support the notion that downregulation of type 1 cannabinoid receptors is a key pathogenic event in Huntington’s disease, and suggest that activation of these receptors in patients with Huntington’s disease may attenuate disease progression. Blázquez, Cristina, et al. «Loss of Striatal Type 1 Cannabinoid Receptors Is a Key Pathogenic Factor in Huntington’s Disease». Brain, vol. 134, n.o 1, enero de 2011, pp. 119-36. https://doi.org/10.1093/brain/awq278. 0006-8950 10.1093/brain/awq278 https://hdl.handle.net/20.500.14352/91567 1460-2156 https://doi.org/10.1093/brain/awq278 Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease