PROJECT: JTC2015: DeCipher

Neurodevelopmental disorders are associated with a significant disease burden and often devastating epilepsies resistant to currently available anticonvulsants. In many cases, molecular genetics have led to an improved understanding of pathogenetic signaling pathways. However, these important advances have so far failed to lead to better therapies. We propose that this is due to our lack of understanding of the mechanisms that underlie hyperexcitability in these disorders. The preliminary data within this consortium suggest a common mechanism underlying hyperexcitability in models of neurodevelopmental disorders, namely, a profound cortical excitation-inhibition imbalance. We will examine this concept in two well-established models of common neurodevelopmental lesions associated with severe epilepsies: a) a model of doublecortex associated with mutations in the doublecortin (DCX) gene with the neuropathological hallmark of aberrantly migrated neurons and (b) a novel model of ganglioglioma, which is the most frequent developmental epilepsy-associated neoplasm and is associated with dysplastic neuronal components. We will examine the neuronal basis of seizure generation in these models using in-vivo electrophysiology and imaging combined with advanced photostimulation and optogenetic techniques. These will allow us to decipher the aberrant connectivity of ‘displaced’ and/or ‘dysplastic’ neurons that underlie the emergence of seizures and derive novel therapy perspectives.