Increased intrinsic membrane excitability is associated with olivary hypertrophy in spinocerebellar ataxia type 1.

One of the characteristic regions of brainstem degeneration across multiple spinocerebellar ataxias (SCAs) is the inferior olive (IO), a medullary nucleus that plays a key role in motor learning. The vulnerability of IO neurons remains a poorly-understood area of SCA pathology. In this work, we address this by evaluating IO disease in SCA1, a prototypic inherited olivopontocerebellar atrophy, using the genetically-precise SCA1 knock-in (SCA1-KI) mouse. We find that these mice exhibit olivary hypertrophy, a phenotype reminiscent of a degenerative disorder known as hypertrophic olivary degeneration (HOD). Similar to early stages of HOD, SCA1-KI IO neurons display early dendritic lengthening and later somatic expansion without frank cell loss. Though HOD is known to be caused by brainstem lesions that disrupt IO inhibitory innervation, we observe no loss of inhibitory terminals in the SCA1-KI IO. Additionally, we find that a separate mouse model of SCA1 in which mutant ATXN1 is expressed solely in cerebellar Purkinje cells shows no evidence of olivary hypertrophy. Patch-clamp recordings from brainstem slices indicate that SCA1-KI IO neurons are hyperexcitable, generating spike trains in response to membrane depolarization. Transcriptome analysis further reveals reduced medullary expression of ion channels responsible for IO neuron spike afterhyperpolarization (AHP)-a result that appears to have a functional consequence, as SCA1-KI IO neuron spikes exhibit a diminished AHP. These findings suggest that expression of mutant ATXN1 in IO neurons results in an HOD-like olivary hypertrophy, in association with increased intrinsic membrane excitability and ion channel transcriptional dysregulation.