Febrile seizures affect up to 5% of children under the age of 5, and are the most common seizures in children of this age group. Current treatment of febrile seizures is limited and inadequate, often resulting in long uncontrolled seizures. Clinical observations suggest a possible etiologic link between early life prolonged febrile seizures and later development of chronic temporal lobe epilepsy. Despite increased risk of epilepsy in children with febrile seizures, these seizures are routinely not treated with anticonvulsants even if they are recurrent. In the past, phenobarbital had been used for over 25 years as prophylaxis in the treatment of recurrent febrile seizures, but anticonvulsant prophylaxis is no longer recommended because side effects appeared to outweigh the potential benefits. One of the main hurdles to the design of effective treatments is that, despite their obvious association with hyperthermia, the detailed molecular mechanisms of febrile seizures remain unclear. This proposal is based on our observation that a temperature dependent increase in intrinsic neuronal excitability driven by L-type voltage-gated calcium channels plays a critical role in the generation of febrile seizures in naive rodents. We will use patch clamp recordings and single-cell RT-PCR from acute slices to characterize the precise molecular identity of the channels involved and test the hypothesis that the same channels are also critical mediators of hyperthermic depolarization in neurons obtained from Scn1atm1Kea mice, an animal model of Dravet syndrome. Further experiments will test the hypothesis that nimodipine can prevent the development of seizures in slices obtained from the Dravet syndrome mice. We will investigate the effect of bath applied nimodipine on the temperature threshold, frequency and magnitude of the epileptic discharges. Finally, we will use behavioral analysis and EEG recordings to test the efficacy of nimodipine for the treatment of seizures in the rodent model of Dravet syndrome. If successful, these experiments may have immediate translational relevance because dihydropyridines have been used for decades in clinical context for the treatment of high blood pressure with negligible adverse effects. Therefore it is likely that the use of nimodipine for the treatment or prevention of febrile seizures would be devoid of negative side effects and that this compound could be used for the treatment of all types of febrile seizures, including those in Dravet patients for which novel pharmacological treatments are badly needed.
The acute therapy of prolonged febrile seizures is largely based on the use of drugs such as phenytoin, which block voltage-gated sodium channels, but certain types of febrile seizures of genetic origin are caused by a sodium channel loss of function and in this case these drugs are ineffective or even counterproductive. This proposal is based on our discovery that hyperthermic seizures are driven by nimodipine-sensitive calcium channels and that nimodipine treatment prevents febrile seizures in nave rodents. We will determine whether the same calcium channels are responsible for the temperature-dependent hyperexcitability in nave animals and in a mouse model of Dravet syndrome and test the efficacy of nimodipine, a drug with excellent safety record, to prevent/stop seizures in the mouse model of Dravet syndrome.
