title: Temperature-sensitive Cav1.2 calcium channels support intrinsic firing of pyramidal neurons and provide a target for the treatment of febrile seizures.
abstract: Febrile seizures are associated with increased brain temperature and are often resistant to treatments with antiepileptic drugs, such as carbamazepine and phenytoin, which are sodium channel blockers. Although they are clearly correlated with the hyperthermic condition, the precise cellular mechanisms of febrile seizures remain unclear. We performed patch-clamp recordings from pyramidal cells in acute rat brain slices at temperatures up to 40°C and found that, at ≥37°C, L-type calcium channels are active at unexpectedly hyperpolarized potentials and drive intrinsic firing, which is also supported by a temperature-dependent, gadolinium-sensitive sodium conductance. Pharmacological data, RT-PCR, and the current persistence in Cav1.3 knock-out mice suggested a critical contribution of Cav1.2 subunits to the temperature-dependent intrinsic firing, which was blocked by nimodipine. Because intrinsic firing may play a critical role in febrile seizures, we tested the effect of nimodipine in an in vivo model of febrile seizures and found that this drug dramatically reduces both the incidence and duration of febrile seizures in rat pups, suggesting new possibilities of intervention for this important pathological condition.
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Radzicki
authors.forename: Hau-Jie
authors.initials: HJ
authors.lastname: Yau
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Pollema-Mays
authors.forename: Lauren
authors.initials: L
authors.lastname: Mlsna
authors.forename: Kangho
authors.initials: K
authors.lastname: Cho
authors.forename: Sookyong
authors.initials: S
authors.lastname: Koh
authors.forename: Marco
authors.initials: M
authors.lastname: Martina
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D019256:Cadmium Chloride / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002934:Cinnamates / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D006624:Hippocampus / Q000473:pathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009553:Nimodipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D003294:Seizures, Febrile / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D013696:Temperature
chemical_list: D000813:Anilides; C485995:Cacna1d protein, mouse; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002934:Cinnamates; C419385:L-type calcium channel alpha(1C); C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D009553:Nimodipine; D019256:Cadmium Chloride