REGION- AND CELL-SPECIFIC CANNABINOID RECEPTOR 1 (CB1R) MODULATION RESCUES MEMORY DEFICITS IN HUNTINGTON´S DISEASE MODELS

Background: Dysregulation of cannabinoid receptor type 1 (CB1R) in the basal ganglia is a well-established hallmark of Huntington’s disease (HD) and has been extensively investigated as a target to alleviate motor symptoms. However, CB1R also plays a critical role in learning and memory. Although cognitive impairments arise early in HD—often preceding motor dysfunction—the contribution of CB1R alterations to these deficits remains poorly understood.
Methods: We examined hippocampal CB1R expression in postmortem human HD tissue and in two HD mouse models (R6/1 and HdhQ7/111, both sexes) using Western blotting, immunohistochemistry, and radioligand binding assays. To restore CB1R function, HD mice received either systemic administration of the CB1R agonist WIN-55,212-2 or hippocampal infusion of viral vectors encoding CB1R. Behavioral, biochemical, electrophysiological, and morphological approaches were employed to assess cognitive function and synaptic integrity.
Results: Human HD samples and both mouse models exhibited a selective reduction of CB1R—but not CB2R—in the hippocampus, accompanied by synaptic alterations and memory deficits. In R6/1 mice, systemic WIN-55,212-2 treatment rescued hippocampal synaptic currents and cognitive performance. CB1R downregulation was restricted to hippocampal GABAergic interneurons and astrocytes. Targeted viral re-expression of CB1R in these cell types was sufficient to restore hippocampus-dependent memory. In primary hippocampal astrocyte cultures, WIN-55,212-2 improved calcium signaling and restored neuronal excitability.
Conclusion: Hippocampal CB1R dysfunction in specific neuronal and glial populations contributes to cognitive deficits in HD. Restoring CB1R signaling represents a promising strategy to mitigate memory impairment, highlighting the therapeutic relevance of region- and cell-specific cannabinoid modulation.