Reversing the curse. Here, the authors show that seizures developped between 3 and 6 month of age in the Subcortical Band Heterotopia rat model of congenital epilepsy. Silencing neurons located in the diseased subcortical band could slow down the progression of epilepsy greatly but it could not reverse it when it was already fully expressed. This suggests that interventions aiming at decreasing the level of excitation of these subcortical heterotopic neurons specifically, if programmed sufficiently early, could improve the pronostic of childhood epilepsy. (by Ingrid Bureau)
Authors: D Hardy *, E Buhler *, D Suchkov *, A Vinck, A Fortoul, F Watrin, A Represa, M Minlebaev & JB Manent (* contributed equally)
Scientific asbtract: Malformations of cortical development represent a major cause of epilepsy in childhood. However, the pathological substrate and dynamic changes leading to the development and progression of epilepsy remain unclear. Here, we characterized an etiology-relevant rat model of subcortical band heterotopia (SBH), a diffuse type of cortical malformation associated with drug-resistant seizures in humans. We used longitudinal electrographic recordings to monitor the age-dependent evolution of epileptiform discharges during the course of epileptogenesis in this model. We found both quantitative and qualitative age-related changes in seizures properties and patterns, accompanying a gradual progression towards a fully developed seizure pattern seen in adulthood. We also dissected the relative contribution of the band heterotopia and the overlying cortex to the development and age-dependent progression of epilepsy using timed and spatially targeted manipulation of neuronal excitability. We found that an early suppression of neuronal excitability in SBH slows down epileptogenesis in juvenile rats, whereas epileptogenesis is paradoxically exacerbated when excitability is suppressed in the overlying cortex. However, in rats with active epilepsy, similar manipulations of excitability have no effect on chronic spontaneous seizures. Together, our data support the notion that complex developmental alterations occurring in both the SBH and the overlying cortex concur to creating pathogenic circuits prone to generate seizures. Our study also suggests that early and targeted interventions could potentially influence the course of these altered developmental trajectories, and favorably modify epileptogenesis in malformations of cortical development.
paru dans Neurobiology of Disease, 2023