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Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis

Abstract

Febrile seizures are frequent during early childhood, and prolonged (complex) febrile seizures are associated with an increased susceptibility to temporal lobe epilepsy. The pathophysiological consequences of febrile seizures have been extensively studied in rat pups exposed to hyperthermia. The mechanisms that trigger these seizures are unknown, however. A rise in brain pH is known to enhance neuronal excitability. Here we show that hyperthermia causes respiratory alkalosis in the immature brain, with a threshold of 0.2–0.3 pH units for seizure induction. Suppressing alkalosis with 5% ambient CO2 abolished seizures within 20 s. CO2 also prevented two long-term effects of hyperthermic seizures in the hippocampus: the upregulation of the Ih current and the upregulation of CB1 receptor expression. The effects of hyperthermia were closely mimicked by intraperitoneal injection of bicarbonate. Our work indicates a mechanism for triggering hyperthermic seizures and suggests new strategies in the research and therapy of fever-related epileptic syndromes.

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Figure 1: Hyperthermia-induced behavioral seizures are associated with brain alkalosis.
Figure 2: Exposure of rat pups to 5% ambient CO2 blocks hyperthermia- and bicarbonate-induced brain alkalosis and associated ictal activity.
Figure 3: Ambient 5% CO2 applied during hyperthermia blocks the long-term upregulation of the Ih current.
Figure 4: Ambient 5% CO2 applied during hyperthermia blocks the long-term upregulation of the CB1 receptors.

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Acknowledgements

We thank M. Heikura and M. Palviainen for technical assistance. This work was supported by grants from the Academy of Finland (to K.K., C.R., J.V.), the Sigrid Jusélius Foundation (to S.S., K.K., J.V., C.R.), the Biocentrum Helsinki Organization (to K.K., C.R.), and the Deutsche Forschungsgemeinschaft (SCHM1383/4-1, SFB665, SFB618, to D.S.). K.K. is a member of the Nordic Center of Excellence, WIRED.

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Schuchmann, S., Schmitz, D., Rivera, C. et al. Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nat Med 12, 817–823 (2006). https://doi.org/10.1038/nm1422

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