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. 2009 Mar 10;106(10):3994-9.
doi: 10.1073/pnas.0813330106. Epub 2009 Feb 20.

Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy

John C Oakley  1 , Franck Kalume, Frank H Yu, Todd Scheuer, William A Catterall
Affiliations

Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy

John C Oakley et al. Proc Natl Acad Sci U S A. .

Abstract

Heterozygous loss-of-function mutations in the alpha subunit of the type I voltage-gated sodium channel Na(V)1.1 cause severe myoclonic epilepsy in infancy (SMEI), an infantile-onset epileptic encephalopathy characterized by normal development followed by treatment-refractory febrile and afebrile seizures and psychomotor decline. Mice with SMEI (mSMEI), created by heterozygous deletion of Na(V)1.1 channels, develop seizures and ataxia. Here we investigated the temperature and age dependence of seizures and interictal epileptiform spike-and-wave activity in mSMEI. Combined video-EEG monitoring demonstrated that mSMEI had seizures induced by elevated body core temperature but wild-type mice were unaffected. In the 3 age groups tested, no postnatal day (P)17-18 mSMEI had temperature-induced seizures, but nearly all P20-22 and P30-46 mSMEI had myoclonic seizures followed by generalized seizures caused by elevated core body temperature. Spontaneous seizures were only observed in mice older than P32, suggesting that mSMEI become susceptible to temperature-induced seizures before spontaneous seizures. Interictal spike activity was seen at normal body temperature in most P30-46 mSMEI but not in P20-22 or P17-18 mSMEI, indicating that interictal epileptic activity correlates with seizure susceptibility. Most P20-22 mSMEI had interictal spike activity with elevated body temperature. Our results define a critical developmental transition for susceptibility to seizures in SMEI, demonstrate that body temperature elevation alone is sufficient to induce seizures, and reveal a close correspondence between human and mouse SMEI in the striking temperature and age dependence of seizure frequency and severity and in the temperature dependence and frequency of interictal epileptiform spike activity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Temperature-dependent seizures in mSMEI. (A) Representative 10-s traces of intracranial EEG activity at the temperature specified. Trace labels correspond to electrode positions in B. The top traces are from a representative P40 wild-type mouse. The bottom traces are from a P32 mSMEI. A seizure was provoked at 39.5 °C. Calibration: 1 s, 1000 μV. (B) A drawing of a mouse cranium with electrode positions indicated. (C) Percentage of P20–46 mSMEI having seizure induced by elevated temperature, 38.0–42.5 °C (wild type, 0%; mSMEI, 90%).
Fig. 2.
Fig. 2.
Age-dependent susceptibility to temperature-induced seizures. (A) Representative 10-s single channel (position 1 in Fig. 1B) EEG traces from P18 Top, P20 Middle, and P32 Bottom at the temperatures indicated. Calibration: 0.5 s, 2000 μV. (B) Percentage of mSMEI remaining free of seizure plotted against body temperature. (C) Mean and distribution of seizure temperatures for P20–22 and P30–46 mSMEI.
Fig. 3.
Fig. 3.
Severity of age-dependent temperature-induced seizures. (A) Mean and distribution of seizure duration. P20–22, 13.3 ± 3.1 s; P30–46, 25.3 ± 1.5 s, P = 0.002. (B) Mean and distribution of seizure-related behavioral severity determined by the Racine score. P20–22, 3.4 ± 0.3; P30–46 mSMEI, 4.6 ± 0.2; P = 0.002). (C) Mean and distribution of average spike frequency during seizure. P20–22, 2.3 ± 0.4 Hz; P30–46, 7.5 ± 0.3 Hz; P = 2.3 × 10−8. (D) Mean and distribution of total number of spikes during seizure. P20–22, 30.6 ± 0.2 spikes; P30–46, 176 ± 13.5 spikes, P = 1.5 × 10−7.
Fig. 4.
Fig. 4.
Temperature dependence of myoclonic seizures in mSMEI. (A) Representative EEG traces in P20 mSMEI during temperature induction of seizures (myoclonic seizures indicated by ∧). Trace labels correspond to electrode positions in Fig. 1B. Calibration: 1 s, 1000 μV. (B) Percentage of mSMEI remaining free of myoclonic seizures plotted against temperature. (C) Mean and distribution of the temperatures at which myoclonic seizures are first seen. P20–22, 40.2 ± 0.3 °C; P30–46, 39.1 ± 0.3 °C; P = 0.02.
Fig. 5.
Fig. 5.
Spontaneous seizures in SMEI. (A) Representative EEG traces from P44 mSMEI showing a spontaneous seizure occurring at normal body temperature. Trace labels correspond to electrode positions in Fig. 1B. Calibration: 5 s, 1000 μV. (B) Mean and distribution of spontaneous seizure duration (38.9 ± 4.2 s). (C) Mean and distribution of average spike frequency during spontaneous seizures (8.9 ± 1.2 Hz). (D) Mean and distribution of total number of spikes during spontaneous seizure (298 ± 70 spikes).
Fig. 6.
Fig. 6.
Interictal spikes in mSMEI. (A) Representative EEG traces in a P22 mSMEI during the temperature-elevation protocol. As temperature is increased, spikes (indicated by *) and at slightly higher temperatures, myoclonic seizures (indicated by ^) are observed. Calibration: 1 s, 1000 μV. (B) Percentage of mSMEI of each age range remaining free of spikes plotted against body temperature. (C) Mean and distribution of body temperatures at which spikes are first observed. P20–22, 39.1 ± 0.4 °C; P30–46 mSMEI, 37.6 ± 0.1 °C; P = 0.0009. All mSMEI were included in the analysis in B, whereas only mSMEI having spikes (P20–22, 8/9; P30–46, 10/11) were included in C.
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