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1In Vivo Electrophysiology, PsychoGenics Inc., Montvale, NJ; 2CHDI Foundation, Inc./CHDI Management, Inc., Los Angeles, CA

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder resulting from an extended number of CAG repeats in the Huntingtin (Htt) gene, for which no disease-modifying therapy is currently available, and comprises several cognitive and affective symptoms, as well as uncontrolled movement (chorea). HD symptoms are thought to be the result of impaired cortico – thalamo – basal ganglia (BG) function; especially a misbalance between the direct and indirect pathways, while the potential dysfunction of the hyperdirect pathway has not been examined. The purpose of the current study was to characterize hyperdirect pathway transmission and its relationship with direct and indirect pathway (dys)function as a contributing factor to HD. We performed in vivo anesthetized electrophysiological extracellular recordings in the anesthetized Q175Het mouse model of HD vs. WT (6 months old).

First, we identified a decreased response of Q175 STN neurons to electrical stimulation of the motor cortex (M1), suggesting impaired hyperdirect pathway transmission. Next, we explored the triphasic response patterns (excitation-inhibition-excitation) of single units in the SNr and/or GP evoked by M1 stimulation, which have been proposed to represent hyperdirect, direct and indirect pathway function, respectively. Our key finding is that in Q175Het mice, the amplitudes for both early and late excitation of SNr neurons to cortical stimulation were significantly decreased compared to WT mice, as revealed from population peristimulus histograms. Our results also revealed that the inhibition phase of SNr neurons was increased in Q175Het but with no change in either latency or duration of the evoked response. For GP neurons in Q175Het mice, amplitudes for both early and late excitation were decreased as in SNr neurons but this did not reach statistical significance. No differences in firing inhibition, response latency or duration were observed. The proportion of neurons showing triphasic responses were decreased for both SNr (39% to 22%) and GP (23% to 19%) in Q175 mice compared to WT mice. Spontaneous firing rates in Q175Het mice showed a modest increase in both SNr and GP neurons compared to the WT but did not reach statistical significance.

These results indicate that a complex dysfunctional interplay between the hyperdirect, direct, and indirect pathways occurs in HD. Genotypic differences established here can be used to monitor basal ganglia circuitry dysfunction in HD models with the potential to evaluate pathway-selective effects of pharmacological treatments.

Study funded by CHDI Foundation, Inc.