Dr Faye McLeod (faye.mcleod@ncl.ac.uk)
Dr Gavin Clowry (gavin.clowry@ncl.ac.uk)
Prof Andrew Trevelyan (andrew.trevelyan@ncl.ac.uk)
Dr Rhys Thomas (rhys.thomas@ncl.ac.uk)
Approximately 1 in 2000 children develop epilepsy before three years of age from a monogenic cause; of these, a third will continue to have seizures into adulthood. The pathological mechanisms often remain obscure, even when causative mutations have been identified, partly because pathology may start in utero, which makes its study extremely difficult. To address these challenges, and study the critical prenatal developmental mechanisms, we have established a novel experimental approach using intact human cortical network, through the Human Developmental Biology Resource (HDBR), to study the developmental consequences of altered prenatal gene expression. We have created living organotypic cultures of the developing human neocortex, in which we can manipulate expression levels of specific genes of interest. We may then examine synaptic development and neuronal network function, using state-of-the-art imaging and electrophysiological techniques. We will also investigate downstream changes in gene expression to identify potential compensatory or pathophysiology modifications. This approach can transform the clinical management of neurodevelopmental conditions in two important ways: by providing a means of validating the pathological consequences of newly identified mutations, and creating a framework for investing gene-therapy to reverse any phenotypic changes.