INVOLVEMENT OF SYNAPSIN GENES IN EPILEPSY AND AUTISM

Epilepsy affects more than 1% of the world’s population and autism spectrum disorder (ASD) affects 1 in 1000 children. ASD begins in the second to third year of life with impaired social interaction, repetitive behaviour, cognitive deficits and abnormal language development, and epilepsy has a distribution with the highest peak in childhood and adolescence. This time frame corresponds to the developmental time period when neuronal circuits are extensively remodelled by experience and suggests a common mechanism for both diseases that are indeed frequently associated. It is believed that seizures in epilepsy and behavioral defects in ASD are the manifestation of abnormalities in the formation and activity of cortical networks. Both epilepsy and ASD have a strong genetic component and considerable progress has been made in the identification of a number of epilepsy- and ASD- associated genes in the human genome. In 2004, a form of familial epilepsy with the onset within the first two decades of life was found to be associated with a non-sense mutation in the gene encoding for synapsin I, a synaptic vesicle protein. More recently, 13 additional mutations in the genes encoding for synapsin I, synapsin II and synapsin III were identified in epilepsy and ASD partly in the frame of our previous Telethon project and partly in collaboration with Drs. Cossette’s and Rouleau’s laboratory in Montreal, Canada. These discoveries represent the first form of genetic epilepsy and ASD linked to a defect in a synaptic vesicle protein. The aim of this project is: (1) to study the properties of the products of mutant human synapsin genes associated with epilepsy/ASD to have insights into the pathogenesis of the diseases; (2) to elucidate, at cellular and circuit levels, the mechanisms that lead to epileptic seizures and ASD in mice in which one or more synapsin genes have been inactivated;and (3) to identify antiepileptic drugs effective on this form of epilepsy in order to develop more powerful therapeutic strategies.