Cell-type specific determinants of epileptogenic cortical malformations – EPIDEV

EPIDEV is a 514k€ basic research collaborative project involving 2 French partners and a Swiss partner over 42 months.

EPIDEV builds on the recently recognized concept that the human brain is a genetic mosaic arising from somatic postzygotic mutations during development. Brain mosaicism is implicated in several neurodevelopmental disorders, including the commonly encountered Focal Cortical Dysplasias (FCD). FCD type 2 (FCD 2) are rare cortical malformations that manifest with refractory childhood-onset epileptic seizures which treatment often necessitate surgical resection of the epileptogenic zone, providing access to cortical tissue.

FCD 2 are caused by brain somatic mutations in the phosphoinositide 3-kinase (PI3K)–AKT–mechanistic target of rapamycin (mTOR) pathway genes, leading to mTOR hyperactivity in a subset of cortical cells.

Hyperactivation of the mTOR signaling in the brain produces a constellation of changes predicted to promote epileptogenesis, but cell-type-specific molecular pathways underlying the pathophysiological features of FCD have not been investigated yet. This proposal will address how can focally scattered mutated neurons cause clinical seizures and what are the developmental molecular features of mTOR-hyperactivated cells in FCD.

We will take advantage of the availability of both an exceptional biobank of human brain specimens (>200 frozen resected tissues with neuropathology and genetic diagnosis) and a preclinical FCD2 mouse model (MTORS2215F mouse). We will use state-of-art multi-modal single-cell transcriptomic profiling approaches and integrating data from both human (Aim 1) and developing mouse cortex (Aim 2), as well as electrophysiology in acute human and mouse cortical slices, but also organotypic cultures.

The scientific program is divided into three Aims: In Aims 1 and 2, we will identify cell-type-specific transcriptional signatures associated with neuronal excitability in human tissue and an established mouse model of FCD, and investigate electrophysiological properties of mTOR-hyperactivated neurons in the developing neocortex. In Aim 3, we will modulate the expression of these genes and attempt to rescue the phenotype on cortical development and seizures in a mouse model and on hyperexcitability in human organotypic cortical slices. Through its original and systematic approach, our proposal will pave the way towards the development of novel targeted therapeutic strategies, less invasive than surgery.

Our consortium is composed of world-leading groups in the fields of epilepsy and cortical neurodevelopment. We master the methodologies used in the project, and we are supported by cutting-edge platforms for sequencing, bioinformatics, genome edition, animal facility, electrophysiology, and imaging that will be necessary during the course of EPIDEV. The proposed tasks and hypotheses rely on original and strong preliminary and published results. Both fundamentally-and clinically-relevant outcomes will be addressed.