Our team investigates the pathophysiological mechanisms of Malformations of Cortical Development (MCDs). MCDs correspond to either macroscopic (e.g. subcortical band heterotopia) or microscopic abnormalities of the cerebral cortex that arise as a consequence of an interruption to the normal steps of formation of the cortical network. Indeed, normal cortical development requires a very precise and orchestrated mobilisation of various neuron subtypes arising from different regions of the brain, and born at various times, in order to achieve specific laminar positioning and connections with other cells. Until the availability of magnetic resonance imaging, MCDs were thought to be extremely rare disorders. It is now recognized that MCDs are a significant cause of epilepsy (20-40% of drug-resistant childhood epilepsies) and intellectual disability (ID), with most patients presenting in childhood. MCDs may be a result of genetic mutations and/or environmental causes such as in utero infection or ischemia. Mutations of many genes linked to several pathways known to regulate neuronal migration and maturation have been recently described in MCD patients, but the physiopathological mechanisms are poorly understood. Our goal is not only to increase our knowledge on genetically determined MCDs, but also to develop more effective therapeutic strategies for treating seizures and other MCDs based on the comprehension of the pathophysiological mechanisms. For this purpose, we conduct integrated multidisciplinary studies involving morphologists, molecular biologists and electrophysiologists. We have also established national and international collaborations with clinicians and geneticists (through the European consortium “DESIRE”, the EPINEXT”–DHU Aix-Marseille University network and the “DECIPHER”-EraNet Neuron funded project) providing us with a transversal appreciation of our researches.
- aMolecular mechanisms that underlie functional cortical network development in health and disease.
- bNeuronal basis of epileptic seizure generation and new therapies.
Molecular mechanisms that underlie functional cortical network development in health and disease.
Our aim is to decipher the mechanisms that control cortical network development through investigation of genetic mutations associated with MCDs. More precisely, we propose to investigate if and how mutations in MCD genes are involved in the morpho-functional changes underlying the development of cortical connections and networks by answering the following questions: i) what are the roles of MCD genes in neuronal migration?; ii) are these genes involved in axon outgrowth, dendritogenesis or synaptogenesis ?; iii) what are the consequences of mutations in MCD genes on morphology and functional maturation of cortical neurons ?
Neuronal basis of epileptic seizure generation and new therapies.
Our group has accumulated several evidence in favor of a common underlying mechanism for altered excitability in MCD rodent models, namely an altered neocortical excitation-inhibition (E/I) balance. Our data also indicate that cortical areas surrounding the heterotopia undergo reactive-type changes that severely modify E/I balance and affect neocortical circuitry, thus contributing to epileptogenesis. Our objectives are to precisely identify the seizure-generating zone, to describe its properties and the mechanisms of seizure generation, and to suggest new therapeutic approaches.