Neuronal network dysfunction at the early stage of epileptogenesis in a genetic model of absence epilepsy

Orateur : Isabelle GUILLEMAIN

Idiopathic Generalized Epilepsies (IGEs) include a set of genetically-determined epileptic syndromes characterized by an early age of onset during childhood. Despite their genetic origin, the epileptogenic processes that govern the occurrence of recurrent generalized seizures in IGEs remain poorly understood. Here, we used a well-recognized model of IGEs, the Genetic Absence Epilepsy Rat from Strasbourg, to investigate the network and cellular mechanisms responsible for the emergence of seizure activity during the post-natal period. We thus performed serial local field potential (LFP) and in vivo intracellular recordings from the second post-natal week to adulthood, in the primary somatosensory cortex (SoCx), the trigger zone for epileptic discharges in mature animals. We found that immature cortical discharges, composed of low-frequency 5-Hz oscillations, first appear in the SoCx at post-natal day 15 and then progressively evolve into typical 7-8 Hz spike-and-wave discharges. The epileptic maturation follows a three-step process, including changes in the morphology of unitary epileptiform LFP component and an increase in the number and duration of cortical discharges. The time-dependent changes in epileptiform activity occurred in parallel with a progressive membrane depolarization of deep-layer pyramidal SoCx neurons, an enhancement of the spontaneous firing rate and a leftward shift in their input-output relation. This age-dependent increase in neuronal intrinsic excitability was accompanied by an increase in the strength of the local synaptic activity together with a growing propensity of neurons to generate synchronized oscillations. These findings demonstrate that the manifestation of recurrent absence seizures results from the progressive acquisition of pro-ictogenic properties in SoCx neurons and networks during the post-natal period. To understand how the cortical somatosensory network activity leads to SWD at this early stage of epileptogenesis we used in vivo two-photon calcium imaging in GAERS pups and age-matched control rats to record simultaneously multiple neurons in the somatosensory cortex. We observed a different scheme of neuronal pairwise connectivity in GAERS, when compared to controls, suggesting abnormal cortical network connectivity.

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