Interneuronal dysfunction in genetic epilepsies: insights from a mouse model of severe myoclonic epilepsy of infancy (SMEI)

The term epilepsies includes several different neurological abnormalities that share as common symptom the epileptic seizure. A large percentage of epilepsies that do not have a recognized aetiology (idiopathic) have a genetic cause. A peculiar form of epilepsy with a poor prognosis is the Severe Mioclonic Epilepsy of Infancy (SMEI). This rare form of epilepsy initiates with febrile seizures and rapidly evolves in an epileptic encephalopathy characterized by recurrent seizures resistant to pharmacological treatment and by a severe cognitive decline. The evaluation of the DNA of these young patients demonstrated an alteration of an ion channel of the neuronal membrane (the voltage-dependent sodium channel), that regulates the basic functions of the cerebral cortex. In spite of the identification of a genetic defect, the mechanisms that determine the phenotypic expression of this epilepsy are still not understood. Recently, a transgenic model of SMEI has been developed by expressing in the mouse the genetic mutation observed in SMEI patients. These animals develop severe epilepsy associated with neurological alterations. The SMEI model is available in the laboratories of Partner 1 and will be utilized by all participants of the consortium to study the pathogenesis of murine SMEI. In particular, it will be tested the possibility (based on preliminary observations) that the defective mutation is expressed mainly in a subpopulation of neurons that have an inhibitory control function on brain activity. The functional abnormality of these inhibitory interneurons could enhance cortical excitability and hence produce epilepsy. We willl also investigate the role of febrile seizures in the development of the severe enkephalopathy typical of SMEI.