Genetic alterations in epilepsy: the cases of Unverricht- Lundborg disease, Fragile X and B1 null mutation

Genetic mechanisms are estimated to underlie about 40% of epilepsies and may present with different manifestations and syndromes. In this thesis, three different cases of genetic implications in epilepsy have been studied: Unverricht-Lundborg disease (ULD), a monogenic Progressive Myoclonic Epilepsy in which disruption of the cystatin B gene results in the manifestation of the pathology; Fragile X, the most frequent genetic mental retardation disease which associates to epileptic seizures in about 25% of the cases; and involvement of the bradykinin system in epilepsy, a possible cause of latent hyper-excitability. The study on ULD revealed increased brain excitability in mice deficient for cystatin B, the genetic defect associated with the pathology. This hyperexcitability seems to be related to a decreased inhibitory cell number and/or to the activation of microglia. Our findings on Fragile-X reveal that, after a chemically induced epileptic event (pilocarpine status epilepticus), active synapses accumulate Fmr1 mRNA and its protein, FMRP. This phenomenon may account for an involvement in activity-dependent synaptic plasticity and epileptogenesis. Finally, we studied bradykinin involvement in brain excitability, and found that electrical (kindling) and chemical (kainate) epileptic insults exacerbate a latent tissue hyper-excitability in B1 null mice. These findings are examples of how genetic alterations may alter brain function, directly or indirectly leading to epilepsy manifestations. In depth, investigation of the different aspects of the genetic mechanisms of epilepsy is very important to identify key factors that, in the end, may allow discovering new therapeutic targets and new treatments. Moreover, study of the basic mechanisms underpinning pathological events may also shed light on the normal brain function.