Figure 7.
IKA blockers normalize PCs firing frequency in SCA1 mice, normalize the motor phenotype of early symptomatic SCA1 mice, and improve the motor phenotype of old SCA1 mice only if administered chronically. a, DiAP normalizes the latency to fall from an accelerated rotarod of 5-week-old SCA1 mice but has no significant effect on 5-week-old control mice (WT NaCl, n = 24; WT DiAP, n = 23; SCA NaCl, n = 24; SCA DiAP, n = 23; WTNaCl vs WTDiAP, p = 0.68; WTNaCl vs SCANaCl, p = 0.0035; WTNaCl vs SCADiAP, p = 0.11; SCANaCl vs SCADiAP, p = 0.04). b, Typical firing pattern of PCs in brain slices from 5-week-old control or SCA1 mice after injection of NaCl or DiAP. c, Firing frequency of PCs from 5-week-old wild-type or SCA1 mice subcutaneously injected with DiAP or saline (WT NaCl, n = 12; WT DiAP, n = 10; SCA NaCl, n = 11; SCA DiAP, n = 8; WT NaCl vs WT DiAP, p = 0.09; WT NaCl vs SCA NaCl, p = 0.0002; WT NaCl vs SCA DiAP, p = 0.14; SCA NaCl vs SCA DiAP, p = 0.03). d, AP normalizes the latency to fall from an accelerated rotarod of 5-week-old SCA1 mice but has no significant effect on 5-week-old control mice (WT NaCl, n = 24; WT AP, n = 23; SCA NaCl, n = 24; SCA DiAP, n = 24; two-way ANOVA followed by Fisher's test, WT NaCl vs WT AP, p = 0.14; WT NaCl vs SCA NaCl, p = 0.0035; WT NaCl vs SCA AP, p = 0.16; SCA NaCl vs SCA AP, p = 0.04). e, Continuous chronic treatment with DiAP using subcutaneous osmotic pumps improves motor performance of 5-week-old SCA1 mice [WT NaCl (n = 20), SCA NaCl (n = 19), SCA DiAP (n = 19), two-way ANOVA followed by Fisher's test, WT NaCl vs SCA NaCl, p = 2 × 10−5; WT NaCl vs SCA DiAP, p = 0.018; SCA NaCl vs SCA DiAP, p = 0.035]. f, Acute treatment with DiAP has no effect on the latency to fall from an accelerated rotarod of 18-week-old SCA1 mice (WT NaCl, n = 13; WT DiAP, n = 11; SCA NaCl, n = 20; SCA DiAP, n = 20; WT NaCl vs WT DiAP, p = 0.11; WT NaCl vs SCA NaCl, p = 0.00004; WT NaCl vs SCA DiAP, p = 7 × 10−7; SCA NaCl vs SCA DiAP, p = 0.21). g, Acute treatment with DiAP has no effect on the grip strength of 18-week-old SCA1 mice (one-way ANOVA followed by Fisher's test, WT NaCl vs WT DiAP, p = 0.43; WT NaCl vs SCA NaCl, p = 1 × 10−10; WT NaCl vs SCA DiAP, p = 2 × 10−9; SCA NaCl vs SCA DiAP, p = 0.49). h, Acute treatment with DiAP has no effect on the latency to fall from a stationary thin rod of 18-week-old SCA1 mice (one-way ANOVA followed by Fisher's test, WT NaCl vs WT DiAP, p = 0.3; WT NaCl vs SCA NaCl, p = 3 × 10−5; WT NaCl vs SCA DiAP, p = 3 × 10−6; SCA NaCl vs SCA DiAP, p = 0.07). i, Firing frequency of PCs from 18-week-old wild-type or SCA1 mice acutely treated with DiAP or saline (WT NaCl, n = 9; WT DiAP, n = 10; SCA NaCl, n = 10; SCA DiAP, n = 15; WTNaCl vs WTDiAP, p = 0.02; WTNaCl vs SCANaCl, p = 0.0003; WTNaCl vs SCADiAP, p = 0.19; SCANaCl vs SCADiAP, p = 0.004). j, Typical firing pattern of Purkinje cells in cerebellar slice from 18-week-old WT and SCA1 mice after acute treatment with saline or DiAP. k, Chronic treatment with DiAP increased the latency to fall from an accelerated rotarod of 18-week-old SCA1 mice (WT NaCl, n = 20; WT DiAP, n = 12; SCA NaCl, n = 18; SCA DiAP, n = 19; WT NaCl vs WT DiAP, p = 0.68; WT NaCl vs SCA NaCl, p = 3 × 10−6; WT NaCl vs SCA DiAP, p = 0.004; SCA NaCl vs SCA DiAP, p = 0.04). l, Chronic treatment with DiAP increased the grip strength of 18-week-old SCA1 mice (WT NaCl vs WT DiAP, p = 0.85; WT NaCl vs SCA NaCl, p = 0.0001; WT NaCl vs SCA DiAP, p = 0.04; SCA NaCl vs SCA DiAP, p = 0.04). m, Chronic treatment with DiAP increased the latency to fall from a stationary thin rod of 18-week-old SCA1 mice (WT NaCl vs WT DiAP, p = 0.64; WT NaCl vs SCA NaCl, p = 3 × 10−5; WT NaCl vs SCA DiAP, p = 0.02; SCA NaCl vs SCA DiAP, p = 0.04). n, Firing frequency of PCs from 18-week-old wild-type or SCA1 mice chronically treated with DiAP or saline (WT NaCl, n = 11; WT DiAP, n = 8; SCA NaCl, n = 22; SCA DiAP, n = 19; WT NaCl vs WT DiAP, p = 0.11; WT NaCl vs SCA NaCl, p = 0.004; WT NaCl vs SCA DiAP, p = 0.25; SCA NaCl vs SCA DiAP, p = 0.03). Error bars indicate SEM. o, Typical firing pattern of Purkinje cells in cerebellar slice from 18-week-old WT and SCA1 mice after chronic treatment with saline or DiAP. *p < 0.05; **p < 0.01; ***p < 0.001.