Leaky Ca²⁺ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice
J. Clin. Invest. Stephan E. Lehnart, et al. 118:2230 doi:10.1172/JCI35346 [Go to this article.]

Figure 2
Epileptic seizures in heterozygous Ryr2^RS/WT mice are inhibited by prevention of the leak via RyR2 channels. (A) Representative EEG and simultaneous ECG (ECG-EEG) recordings from a WT littermate mouse, showing normal brain activity and a normal cardiac SR; and (B) a heterozygous Ryr2^RS/WT mouse during an interictal period without epileptiform activity, showing normal brain activity and a normal sinus heart rhythm. (C) Recordings from an Ryr2^RS/WT mouse during an ictal episode, showing abnormal EEG activity but a normal cardiac rhythm (sinus tachycardia). The recorded seizure began with the Straub tail sign (single asterisk), followed by generalized tonic-clonic seizure (double asterisks), then spiking activity that gradually increased in amplitude and rhythmicity and ended with a depressed electric postictal period characterized by relaxed muscle tone, indicating end of seizure (triple asterisks). Consecutive 8-second traces from one EEG channel (left hemisphere) are shown; there was no difference in the spiking patterns between the left and right hemispheric activity; and (D) EEG recording during a postictal period with epileptiform activity (arrows). (E) Average latency to development of generalized tonic-clonic seizures and overall seizure score comparison in WT and Ryr2^RS/WT mice following 4-AP and CAF susceptibility testing. *P < 0.05. (F) Average latency to development of generalized tonic-clonic seizures and overall seizure score comparison in Ryr2^RS/WT mice treated with S107 subjected to a seizure protocol identical to that in E, showing that S107 partially protects against seizures. *P < 0.03 (left); *P < 0.04 (right). (G) Morphology of seizure-like events recorded from CA3 region of hippocampal slices incubated in 10 μM 4-AP from WT (n = 4) and Ryr2^RS/WT (n = 4) mice shown at low and high time resolution. Short bars above traces indicate portion of recording that is expanded in the lower traces. (H) Histogram analysis of number of spikes per burst, showing longer bursts in the Ryr2^RS/WT compared with WT mice. (I) Bar graphs showing analyses of complex burst activity only (defined as more than 10 spikes per burst, consistent with seizure-like activity). Left: Frequency per minute of complex bursts; middle: frequency of spikes per minute per complex burst; right: average number of spikes per complex burst, all of which were significantly elevated in Ryr2^RS/WT compared with WT mice. *P < 0.005; ^†P < 0.0001, ^#P < 0.001.