Figure 7. Ion channel expression is disrupted in the SCA1-KI medulla.

(A) Transcriptomic analysis of whole medulla from SCA1-KI and wild-type mice at 28 weeks reveal that 31 ion channel genes are differentially expressed. Of these, 25 influence excitability intrinsically (IC_intrinsic), while 6 influence excitability synaptically (IC_synaptic). (B) Downregulation of Atxn1 expression by antisense oligonucleotides (ASOs) ameliorates brainstem phenotypes in SCA1-KI mice. Of the 1374 differentially expressed genes (DEGs) in the SCA1-KI medulla, 317 DEGs were significantly rescued by ASO treatment (and, therefore, are more likely to be responsible for the observed phenotypic rescue). Within this cohort, IC_intrinsic genes were significantly enriched. (C) Heatmap showing differential expression of the 10 IC_intrinsic DEGs between treatment groups. These ion channel genes exhibited a significant increase in expression after ASO treatment (left), with the majority of them rising to wild-type levels (right). (D) In order to examine how decreases in medullary ion channel transcripts may result in a loss of channels in the IOPr, immunostaining for the small-conductance potassium channel SK2 was performed. Coronal histological sections of the IOPr in wild-type (top) and SCA1-KI (bottom) mice at 14 weeks (an early symptomatic timepoint) are shown. Sections have been stained for SK2 (green) and calbindin (red). (E) Quantification of immunostaining reveals a significant loss of SK2 channels on the membrane of SCA1-KI IOPr neurons. Data are expressed as mean ± SEM. Statistical significance derived by Fischer’s exact test (enrichment analyses) or unpaired t-test with Welch’s correction (all other comparisons), ** = P < 0.01, ns = not significant. (A–C) N_{wild-type, Vehicle} = 8 mice, N_{SCA1-KI, Vehicle} = 8 mice, N_{SCA1-KI, ASO} = 7 mice. (D, E) Nwild-type = 6 mice, N_SCA1-KI = 6 mice.