a–h Conditional α2-Na/K ATPase knockout mice (cKO) and Ctrl mice were monitored for spontaneous cortical spreading depression (sCSD) events in intrinsic optical signal imaging for total hemoglobin, with GCaMP6f imaging for neuronal calcium in a subset, and right hemispheric EEG recording (n = 6 Ctrl, 6 cKO mice, 3 male and 3 female, 81 Ctrl and 75 cKO hours). Frequency of sCSD events in cKO and Ctrl mice (b). No sCSD events were observed in Ctrl mice. Data are presented as mean ± s.e.m. *P < 0.05 (two-tailed t test, n = 6 mice per group, P < 0.0001). Table of all observed sCSD events (c). LVA low-voltage activity. Green box indicates pictured sCSD7 (d–f). The position-time plots for example sCSD in d with propagation of signal over time is shown in e. The shaded box on f corresponds to the time captured by the still images (d) and the black bar (e, total time = 90 s, start at 50 s, 10 s between images). g–k cKO and Ctrl mice were monitored for low-voltage activity (LVA) events with continuous bilateral EEG and video monitoring. Frequency of observed LVA events in conditional cKO and Ctrl mice (h). No LVA events were observed in Ctrl mice. Data are presented as mean ± s.e.m. *P < 0.05 (two-tailed t test, n = 6 Ctrl mice—3 male, 3 female, 7 cKO—5 male, 2 female, P < 0.0001). Frequency of LVA events in cKO mice (h) does not differ from frequency of sCSD events (b, two-tailed t test, P = 0.1307). An example LVA event (i). Shaded box indicates LVA in right and left hemispheres, green trace indicates paralysis. LVA events in cKO mice correlated with abnormal motor behavior (j). Proportions of normal (eating, sleeping, and walking) and abnormal behavior (abnormal posture, abnormal walking, and paralysis) in cKO mice during normal EEG and LVA events. ***P < 0.001 (Chi-squared test, n = 130 events in seven mice each, P < 0.0001). Breakdown of behaviors during normal EEG and LVA, and unilateral vs. bilateral LVA (abnormal behavior = colors, normal behavior = grayscale, n = 130 events, 62 unilateral 68 bilateral, in seven mice) (k).