Upregulation of endocannabinoid signaling in vivo restores striatal synaptic plasticity and motor performance in Huntington's disease mice

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Abstract
Background: Synaptic dysfunction underlies early sensorimotor and cognitive deficits in Huntington's disease (HD) and precedes the degeneration of striatal spiny projection neurons and cortical pyramidal neurons. Movement selection and motor learning, which are impaired early in HD, are regulated by connections between the motor cortex, basal ganglia and thalamus. In particular, plasticity at corticostriatal synapses, including endocannabinoid-mediated long-term depression (LTD), is critical for motor learning. Previously, we found impaired endocannabinoid-mediated LTD, induced by high frequency stimulation (HFS) at corticostriatal synapses in brain slice recordings from pre-manifest HD mouse models, which was corrected by JZL184, an inhibitor of endocannabinoid 2-arachidonoyl glycerol (2-AG) degradation. Objective: Determine the effects of in vivo JZL184 administration on YAC128 HD model and wild-type (WT) littermate mice. Methods: JZL184 was administered to mice orally over a 3-week period and their motor function was assessed using several behavioral tasks. In addition, brain tissue was collected from mice in order to quantify changes in endocannabinoid levels and measure HFS-induced plasticity at corticostriatal synapses. Results: Oral administration of JZL184 significantly increased levels of 2-AG in striatal tissue. While JZL184 treatment had no impact on open field behavior, the treatment eliminated the difference in motor learning on the rotarod task between YAC128 and WT mice. Moreover, HFS-induced striatal plasticity in YAC128 mice was normalized to WT levels after JZL184 treatment. Conclusions: These results suggest a novel target for mitigating early symptoms of HD and support the need for clinical trials of therapies that modulate the endocannabinoid system.
Funding Information
  • Canadian Institutes of Health Research (PJT-178043)
  • Huntington Society of Canada
  • Canadian Institutes of Health Research

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