Malformation of cortical development: the genesis of epileptogenic networks
Malformations of cortical development (MCDs) result from alterations of one or combined developmental steps, including progenitors proliferation, neuronal migration and differentiation. They are important cause of childhood epilepsy and frequently associate cognitive deficits and behavioral alterations. Though the genetic basis of MCDs have known prominent progress during the past decade, including the identification of somatic, mosaic mutations responsible for focal MCDs, the pathophysiological mechanisms linking malformations to epileptogenesis remain elusive. In this seminar I will present data from my team and from the literature addressing this topic in two different MCDs types, the subcortical band heterotopia as a model of cortical migration defect and mTOR- dependent MCDs , that characterize by cortical dyslamination and neuronal differentiation defects.
Misplaced and misconnected: circuit-level defects in malformations of cortical development
During histogenesis of the cerebral cortex, a proper laminar placement of defined numbers of specific cellular types is necessary to ensure proper functional connectivity patterns. There is a wide range of cortical malformations causing epilepsy and intellectual disability in humans, characterized with various degrees of neuronal misplacement, aberrant circuit organization or abnormal folding patterns. Although progress in human neurogenetics and brain imaging techniques have considerably advanced the identification of their causative genes, the pathophysiological mechanisms associated with defective cerebral cortex development remain poorly understood. In my presentation, I will outline some of our recent works in rodent models illustrating how misplaced neurons forming grey matter heterotopia, a cortical malformation subtype, interfere with the proper development of cortical circuits, and induce both local and distant circuitry changes associated with the subsequent emergence of epilepsy.