Climbing fibers (CFs) generate complex spikes (CS) and Ca²⁺ transients in cerebellar Purkinje cells (PCs), serving as instructive signals. The so-called 'all-or-none' character of CSs has been questioned since the CF burst was described. Although recent studies have indicated a sensory-driven enhancement of PC Ca²⁺ signals, how CF responds to sensory events and contributes to PC dendritic Ca²⁺ and CS remains unexplored. Here, single or simultaneous Ca²⁺ imaging of CFs and PCs in awake mice revealed the presynaptic CF Ca²⁺ amplitude encoded the sensory input’s strength and directly influenced post-synaptic PC dendritic Ca²⁺ amplitude. The sensory-driven variability in CF Ca²⁺ amplitude depended on the number of spikes in the CF burst. Finally, the spike number of the CF burst determined the PC Ca²⁺ influx and CS properties. These results reveal the direct translation of sensory information-coding CF inputs into PC Ca²⁺, suggesting the sophisticated role of CFs as error signals.

Somatic expansion of the Huntington’s disease (HD) CAG repeat drives the rate of a pathogenic process ultimately resulting in neuronal cell death. Although mechanisms of toxicity are poorly delineated, transcriptional dysregulation is a likely contributor. To identify modifiers that act at the level of CAG expansion and/or downstream pathogenic processes, we tested the impact of genetic knockout, in Htt^Q111 mice, of Hdac2 or Hdac3 in medium-spiny striatal neurons that exhibit extensive CAG expansion and exquisite disease vulnerability. Both knockouts moderately attenuated CAG expansion, with Hdac2 knockout decreasing nuclear huntingtin pathology. Hdac2 knockout resulted in a substantial transcriptional response that included modification of transcriptional dysregulation elicited by the Htt^Q111 allele, likely via mechanisms unrelated to instability suppression. Our results identify novel modifiers of different aspects of HD pathogenesis in medium-spiny neurons and highlight a complex relationship between the expanded Htt allele and Hdac2 with implications for targeting transcriptional dysregulation in HD.