Abnormal sensitivity to cannabinoid receptor stimulation might contribute to altered gamma-aminobutyric acid transmission in the striaturn of R6/2 Huntington's disease mice

Background: One of the earliest neurochemical alterations observed in both Huntington; disease (HD) patients and HD animal models is the dysregulation of the endocannabinoid system, an alteration that precedes the development of identifiable striatal neuropathology. How this alteration impacts striatal synaptic transmission is unknown. Methods. We measured the effects of cannabinoid receptor stimulation on gamma-aminobutyric acid (GABA)-ergic synaptic currents recorded from striatal neurons of R6/2 HD mice in the early phase of their disease. Results. The sensitivity of striatal GABA synapses to cannabinoid receptor stimulation is severely impaired in R6/2 HD mice. In particular, whereas in control animals activation of cannabinoid CB1 receptors results in a significant inhibition of both evoked and spontaneous GABA-mediated synaptic events by a presynaptic mechanism, in R6/2 mice this treatment fails to reduce GABA currents but causes, in contrast, a slight increase of spontaneous inhibitory postsynaptic currents (sIPSCs). Conclusions: Experimental HD was also associated with enhanced frequency of sIPSCs, a result consistent with the conclusion that loss of cannabinoid-mediated control of GABA transmission might contribute to hyperactivity of GABA synapses in the striatum of HD mice. Accordingly, spontaneous excitatory postsynaptic currents, which were not upregulated in R6/2 mice, were still sensitive to cannabinoid receptor stimulation.