Effect of chronic upregulation of endocannabinoid signaling in vivo with JZL184 on striatal synaptic plasticity and motor learning in YAC128 Huntington disease mice

Synaptic dysfunction underlies early sensorimotor and cognitive deficits, and precedes neurodegeneration in a variety of disorders, including Alzheimer, Parkinson and Huntington disease (HD). A monogenic inherited disorder, HD manifests with cognitive, motor and mood disorders associated with progressive degeneration of striatal spiny projection neurons and cortical pyramidal neurons. Cortico-basal ganglia-thalamic loops regulate movement selection and motor learning, which are impaired early in HD. Skilled motor learning is mediated in part by plasticity at cortico-striatal synapses, including endocannabinoid-mediated, high-frequency stimulation induced long-term depression (HFS-LTD). Previously, we found impaired HFS-LTD 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. Here, we tested the effects of JZL184 administered in vivo to YAC128 HD model and wild-type (WT) littermate mice. JZL184, given orally daily over a 3-week period, significantly increased levels of 2-AG in striatal tissue. While JZL184 treatment had no impact on open field behavior which was similar for the two genotypes, the treatment improved motor learning on the rotarod task in YAC128 mice to the level observed in WT mice. Moreover, HFS-induced striatal plasticity measured by field potential recording in acute brain slice from YAC128 mice was normalized to WT levels after JZL184 treatment. These results suggest a novel target for mitigating early symptoms of HD, and support the need for clinical trials to test the efficacy of modulating the endocannabinoid system in treatment of HD.