Authors :
Presenting Author: Athénaïs Genin, PhD Student – Institut de génomique fonctionnelle - CNRS - INSERM
Alicia Janvier, Ingineer – Institut de Génomique Fonctionnelle
Alexis Chaussy, Ingineer – Institut des Neurosciences de Montpellier
Marine Blaquière, Ingineer – Institut de Génomique Fonctionnelle
Massimo Mantegazza, PhD – Institut de Pharmacologie Moléculaire et Cellulaire
Fabrice Duprat, PhD – Institut de Pharmacologie Moléculaire et Cellulaire
Etienne Audinat, PhD – Institut de Génomique Fonctionnelle
Nicola Marchi, PhD – Institut de Génomique Fonctionnelle
Noémie Cresto, PhD – Institut de Génomique Fonctionnelle
Rationale:
Dravet syndrome (DS) is a genetic disorder characterized by severe, early and drug-resistant epileptic seizures in childhood and subsequent lifelong cognitive and behavioral disorders including memory deficits. DS is mainly caused by heterozygous de novo mutations in the Nav1.1 sodium channel (SCN1A gene), which is primarily responsible for action potentials in inhibitory interneurons. Although this mutation is responsible for the first epileptic seizures in childhood, the progression of epileptic activity and the onset of cognitive disorders are poorly understood and remain without effective treatment. However, our understanding of DS is mostly based on neurocentric studies that did not take into account the other cellular types influencing neuronal activity. Astrocytes, key regulators of neuronal activity, have been implicated in the pathogenesis of epilepsy and cognitive deficits, but their roles in DS remain unknown. We hypothesized that early epileptic seizures in DS could durably modify astrocytes, disrupting their interactions with neurons, thus participating in the unfavorable functional remodeling that occurs during DS progression.
Methods:
To test this hypothesis, we use a heterozygous SCN1A knockout mouse model that recapitulates the main features of DS, including an early epileptic phase (postnatal day 20 (P20) to P30) and a long-term phase (P90) marked by chronic epilepsy, cognitive and behavioral deficits. By combining quantitative PCR, histology, and electrophysiology techniques on hippocampal slices, we analyzed astrocytic changes during DS and their possible effects on hippocampal synaptic activity (Schaffer collaterals (SC) – Cornu Ammonis 1 synapse (CA1)).
Results:
Our results show that the early, intense phase of DS epileptic seizures leads to hippocampal astrocytic reactivity characterized by morphological changes, increased expression of glial fibrillary acidic protein and proliferation. This reactivity is maintained over the long term (P90) with a 60% increase in hippocampal astrocytic coupling via GAP junctions, representing a biomarker of the network's persistent adaptation to DS progression. Astrogliosis during the chronic phase of DS is also associated with increased expression of interleukin-6 (IL-6) in the hippocampus, but not other proinflammatory cytokines. IL-6 is primarily produced by reactive astrocytes and has been closely associated with synaptic dysfunction related to seizure severity and memory deficits in other models. For now, our studies show that that this increased reactive astrocyte network is not associated with impaired basal transmission of the SC-CA1 synapse but appears to be associated with excessive neurotransmitter release during high-frequency stimulation.
Conclusions:
Our results suggest that previously unknown astrocytic changes may contribute to the progression of DS and that IL-6 could be a promising therapeutic target for modifying the trajectory of the disease.
Funding: - Valérie Chamaillard Grant 2023 from the French Foundation for Epilepsy Research (€50,000)
- Funding from the French National Research Agency named “DS Remo” in 2024 (€252,732.42)