Study of a mouse model heterozygously carrying a pathogenic variant of the KCNQ2 gene associated with early epileptic and developmental encephalopathies
Najoua Maazou Biba

Equipe “Epilepsies développemntales”

Abstract : Epileptic and developmental encephalopathies (EED) are a group of severe and intractable diseases in which severe epilepsy is associated with an alteration of cognitive/sensory and motor functions. The pathophysiological mechanisms of EED are still unknown. However mutations of several genes have been identified and in particular in the KCNQ2 gene which plays major role in EDE with neonatal onset. KCNQ2-related EED are characterized by epileptic seizures occurring at birth and an intercritical EEG pattern known as “suppression burst”. Although seizures usually resolve during development, cognitive/motor deficits persist. KCNQ2 encodes the Kv7.2 subunit of the potassium Kv7 channels responsible for the M current which activation limits neuronal excitability. The p.T274M variant of KCNQ2/Kv7.2 has been frequently identified in EED patients. A mouse harboring this variant has recently been generated. Behavioral analyses show that these mice displayed a deficit in learning and spatial memory in adulthood. The aim of my thesis was to study the electrophysiological consequences of this variant both in vivo using EEG recordings and ex-vivo using patch-clamp recordings of pyramidal cells of the motor cortex during development. In vivo, I observed that these mice displayed epileptic seizures which occurrence decreased during development. Ex vivo, IM was reduced and pyramidal cells excitability increased. These changes were first observed in layers II/III pyramidal cells and later in layer V pyramidal cells. In addition, I observed a large increase in network activity carried by GABA. However, the effects of the variant on electrophysiological activity were observed during a limited period of development suggesting that a compensatory mechanism take place allowing the recovery of a physiological activity. I propose that this compensation is the cause of the remission of seizures and that the cognitive deficits are not the result of a durable alteration of M current.

Jury

Massimo Mantegazza, rapporteur – IPMC UMR727, Valbonne
Jérôme devaux, rapporteur – Institut des Neurosciences de Montpellier U1051
Frederic brocard, examinateur – INT NEUROSCIENCES, Marseille
Rima Nabbout, Examinatrice –  Service de neurologie pédiatrique, Hôpital Necker-Enfants Malades, Paris
Igore Medina, Président – Inmed U1249, Marseille
Laurent Aniksztejn, Directeur de thèse – Inmed U1249, Marsille

Tuesday 20 December 2022 at 2pm, Inmed conference room