Molecular and circuits bases of epileptogenic mosaic cortical malformations
The human brain is a genetic mosaic resulting from frequent somatic mutations during development. Somatic mosaicism cause Focal Cortical Dysplasias (FCD), a brain malformation manifesting with childhood drug-resistant epilepsy. FCD is characterized by cortical disorganization as the result of abnormal migration and differentiation of neurons. Here, we aim at understanding the molecular and circuit bases of FCD by combining in vitro and in vivo approaches in mouse and human. Although mutations in mTOR pathway genes are an important cause of FCD, etiology often remains unidentified. In Aim 1, using an in vivo genome-wide screen, we will identify genes and enhancers involved in neuronal mismigration in the mouse neocortex, giving special attention to mTOR signaling pathway components. In Aim 2, using in vivo c-Fos mapping of circuit activity, live EEG-video monitoring in mice, and single-cell transcriptional analyses, we will functionally interrogate Aim 1 candidates and identify those causing abnormal circuit activity and seizures. In Aim 3, we will take advantage of our human FCD specimen biobank to identify mosaic somatic mutations in the non-coding regions and genes of Aim1. We will use human iPSCs-derived cortical organoids to identify the developmental mechanisms at play in FCD and provide proof-of-principle functional rescue. Hence, ultimately, this proposal will pinpoint druggable targets toward a precision medicine approach.
Gene targeting in the brain, Stem cells and neural differentiation/cell therapy, Molecular modelling techniques, Electrophisiological approaches, omics approaches, Cortical malformations, Patient cohorts, Animal studies, Epilepsy, somatic mosaicism, genome-wide screens
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Stéphanie Baulac (Coordinator)