DS0407 -

Deciphering cortical epileptic network dysfunction during brain development in idiopathic epilepsy – SoAbsence

Submission summary

Although most idiopathic epilepsies develop during brain maturation, the physiopathological mechanisms responsible for the building of epileptic networks remain unknown. The identification of such mechanisms is critical for a better understanding of normal and pathological development of cortical networks and to develop innovative prophylactic treatments. Absence epilepsy (AE) is the prototypic form of idiopathic/genetic epilepsy that develops during postnatal brain maturation. Using the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) model, we demonstrated that spike-and-wave discharges (SWD), the EEG hallmark of absence seizures, originate from the somatosensory cortex (SoCx) where they first occur around the 25th postnatal day. We also demonstrated that the appearance of SWD is preceded by the emergence of abnormal oscillatory cortical discharges two weeks after birth. This progressive maturation of cortical discharges is accompanied by an age-dependent modulation of the electrophysiological properties of deep layers pyramidal neurons of the SoCx (i.e., ictogenic neurons), associating an increased intrinsic excitability and a growing propensity to generate synchronized oscillations. Altogether, these recent data suggest that an abnormal development of SoCx neuronal networks in epileptic animals, leading to an altered anatomical and/or functional connectivity, could be responsible for the emergence of paroxysmal activities after brain maturation. The main objective of SoAbsence is therefore to determine, at the cellular and network level, the functional and morphological processes leading to the progressive emergence of SWD in AE. To this aim, we will track the changes that occur in SoCx neurons and networks between 15 and 30 days after birth in the GAERS model, using an array of methodologies combining measurements of functional connectivity (multichannel local field potential, two-photon calcium imaging, intracellular electrophysiological recordings, laser scanning photostimulation with glutamate uncaging) as well as structural connectivity (single neuron labeling, tracing of connections between postsynaptic neurons and their first-order presynaptic partners by rabies virus-based method) of SoCx circuits. The key findings of this project will be challenged in another rodent polygenic model of AE (WAG/Rij rats) to ensure that our data can be generalized to different forms of AE. All the technical approaches are mastered and routinely used by the different partners of SoAbsence who also have a solid expertise in epilepsy and/or sensory neural circuits. This project should permit to identify and characterize the post-natal cellular and/or network dysfunctions associated with the emergence of recurrent generalized seizures in childhood idiopathic epilepsies. The scientific impact of SoAbsence is expected to be high because, in addition to bring new knowledge on the development of connectivity in a sensory system during brain maturation, this proposal has the potential to have a clinical impact by improving the diagnosis of AE and other idiopathic epilepsies. SoAbsence has also a potential therapeutical impact by providing new targets to treat idiopathic epilepsies before their development.

Project coordination

Antoine DEPAULIS (Institut National de la Santé et de la Recherche Médicale - Grenoble Institut des Neurosciences)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM UMR_S1127 Institut National de la Santé et de la Recherche Médicale
INMED Institut de neurobiologie de la méditerranée
GIN - Inserm 1216 Institut National de la Santé et de la Recherche Médicale - Grenoble Institut des Neurosciences

Help of the ANR 529,862 euros
Beginning and duration of the scientific project: February 2017 - 48 Months

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