Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis.
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 I(h) 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.
Schuchmann
Sebastian
S
Department of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 1 (POB 65), 00014 Helsinki, Finland.
Schmitz
Dietmar
D
Rivera
Claudio
C
Vanhatalo
Sampsa
S
Salmen
Benedikt
B
Mackie
Ken
K
Sipilä
Sampsa T
ST
Voipio
Juha
J
Kaila
Kai
K
D000472:Alkalosis, Respiratory / Q000139:chemically induced / Q000503:physiopathology*; D000818:Animals; D001639:Bicarbonates; D001831:Body Temperature; D001921:Brain / Q000254:growth & development / Q000503:physiopathology; D002245:Carbon Dioxide / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D005334:Fever / Q000503:physiopathology* / Q000517:prevention & control; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D003294:Seizures, Febrile / Q000503:physiopathology*
D001639:Bicarbonates; D002245:Carbon Dioxide