Figure 3.

H/+ mice exhibit age-related motor dysfunction and seizure susceptibility

(A and B) At 6 months of age, H/+ mice exhibit a severe hindlimb clasping phenotype (A) with longer bouts of clasping (B). +/+ mice, n = 29; H/+ mice, n = 24.

(C) H/+ mice at 6 months old also show reduced hind paw stance width as assessed by paw-print analysis of gait. +/+ mice, n = 12; H/+ mice, n = 19.

(D and E) H/+ mice show impaired performance on the rotarod. H/+ mice exhibit increasingly impaired performance on the accelerating Rotarod relative to +/+ at both 4 and 6 month time points. +/+ mice, n = 12; H/+ mice, n = 12. As described in the method details, each mouse was tested on the rotarod in 4 repeated test sessions (D), and the average measure obtained across the 4 sessions is plotted (E).

(F) At age 6 months, approximately 30% H/+ mice (compared to 5% +/+ mice) cannot traverse the ledge of the home cage during the ledge test. Among mice that are able to complete the traversal, H/+ mice show a higher severity score. +/+ mice, n = 19; H/+ mice, n = 20.

(G) H/+ mice exhibit impaired performance on the elevated beam walking test. H/+ mice made progressively more hindlimb foot faults while traversing a beam of two different diameters with increasing age relative to performance of age-matched +/+ littermate controls (G). Shown is summary data indicating that H/+ mice exhibited progressively more foot faults with age. +/+ mice, n = 12; H/+ mice, n = 12. Each mouse walked on the elevated beam 3 times.

(H) Spontaneous seizures in H/+ mice. Shown on the top is a representative example of an EEG trace from a 6-month-old H/+ mouse demonstrating a seizure event. On the bottom are the summary data indicating the number of seizure events occurring each day during a 7 day recording period of four H/+ mice. Dataset includes two males and two females.

(I) H/+ mice at P16–P21 were susceptible to audiogenic seizure, either with a high-intensity (top; siren; +/+ mice, n = 48; H/+ mice, n = 53) or a high-frequency stimulus (bottom; sonicator; +/+ mice, n = 17; H/+ mice, n = 20).

(J) H/+ mice are more sensitive to PTZ-induced kindling relative to their +/+ siblings as demonstrated by the PTZ seizure threshold test (see STAR Methods). +/+ mice, n = 11; H/+ mice, n = 13. See also Figure S4. Data are presented as mean ± SEM.

Statistical analyses: unpaired Student’s t test (B, C, E, and F), two-way ANOVA with Šídák’s multiple comparisons test (D and G), Mantel-Cox test (J), and Fisher’s test, intensity: p = 0.0001, frequency: p = 0.1886 (I). ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, and ∗∗∗∗p < 0.0001. Exact p values can be found in Table S1.