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G. C. TOMBAUGH, S. GELMAN, A. BRADAIA, K. WADEL, V. GARDES, C. TOULLER, A. SERS, A. GHAVAMI, B. BUISSON, G. BATES, M. MIELCAREK, C. DOMINGUEZ, M. MAILLARD, V. BEAUMONT

Huntington’s disease (HD) is a lethal autosomal dominant neurodegenerative disorder that leads to deficits in motor control widely believed to reflect structural and/or functional changes in neurons of the basal ganglia. In-vitro brain slice recordings of both the R6/2 and Q175 mouse models of HD have revealed a paucity of glutamatergic innervation of the striatum as well as alterations in intrinsic membrane properties of striatal medium spiny neurons (MSNs, exemplified by a large increase in membrane resistance (Rm) and a reduced rheobasic current (Rh). Such changes are reflective of corticostriatal pathway degeneration and MSN hyper-excitability and are likely to result in aberrant striatal output. A 50 % reduction in HDAC4 restored these and other electrophysiological changes in both the R6/2 model, a transgenic over-expresser of Exon 1 HTT with an expanded polyglutamine repeat, and heterozygous Q175 knock-in mice (Q175 +/-), which carry one normal and one mutant HTT allele with an expanded repeat of ~190 polyglutamines, in addition to reversing behavioral alterations in R6/2 mice (Mielcarek et al, 2013; PLOS Biology, in press).

We examined MSN properties in R6/2 mice and Q175 heterozygous knock-in mice (Q175 +/-) after sub-chronic in vivo exposure (4 weeks or 4 months respectively) to a novel selective Class IIa HDAC inhibitor, CHDI-00390576, to evaluate whether this could mimic the genetic HDAC4 knockdown data. MSNs in R6/2, Q175 and WT mice had nearly identical resting membrane potentials, but R6/2 and Q175 MSNs exhibited significantly elevated Rm and lower Rh. Rm in both models was partially reversed by CHDI-00390576, while Rh was partially reversed in R6/2 but not significantly in Q175. Neither Rm nor Rh was affected in drug-treated WT mice. Action potential amplitude and threshold in the HD models were decreased and increased, respectively, relative to WT controls. These changes, which were reversed in HDAC4 knockdown Q175 mice, were unaffected in drug-treated R62 mice. In R62 and Q175 (+/-) mEPSC frequency was significantly lower compared to WT MSNs, but no drug-related rescue was seen for either measure. In contrast, reduced mEPSC frequency was reversed by HDAC4 knockdown in both R62 and Q175.

Our findings indicate that disease-specific HD phenotypes in MSNs can be partially reversed by manipulating HDAC4 activity/expression in R6/2 and Q175 mice, suggesting a therapeutic potential for Class IIa HDAC inhibitors in HD.