Long-lasting astrocyte remodeling in Dravet Syndrome Scn1a+/- mouse model.

Genin, A.; Janvier, A.; Moujellil-Legagneur, T.; Blaquiere, M.; Chaussy, A.; Prive, R.; Duprat, F.; Mantegazza, M.; Audinat, E.; Marchi, N.; Cresto, N.

doi:10.64898/2026.01.06.697745

bioRxiv · 10.64898/2026.01.06.697745

Long-lasting astrocyte remodeling in Dravet Syndrome Scn1a+/- mouse model.

Genin, A.·Janvier, A.·Moujellil-Legagneur, T.·Blaquiere, M.·Chaussy, A.·Prive, R.·Duprat, F.·Mantegazza, M.·Audinat, E.·Marchi, N.·Cresto, N.

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Abstract

BackgroundDravet syndrome (DS) is a prototypical developmental and epileptic encephalopathy caused by SCN1A gene mutations leading to NaV1.1 loss of function. The latter causes early-onset drug-resistant seizures and enduring cognitive and behavioral deficits. In this pathological context, the implication of astrocytes remains insufficiently explored. MethodsUsing a heterozygous Scn1a knock-out (Scn1a/-) mouse model that recapitulates the DS-human phenotype, we examine astrocyte remodeling at landmark disease stages, as defined by video-EEG and behavioral read-outs. ResultsFrom initial disease aggravation (PN20-35) to long-term stabilization (up to PN90), Scn1a/- mice showed increased hippocampal and cortical GFAP transcript and protein levels, compared to age-matched control littermates and to an earlier presymptomatic (<PN20) time point. During the aggravation phase in Scn1a/- mice, astrocyte branching, revealed by GFAP histological analysis and by intracellular delivery of Alexa Fluor 488 in hippocampal slices was increased but not sustained long-term. These disease-stage-dependent astrocyte modifications were not associated with macroscopic hippocampal sclerosis or cortical atrophy. To further study astrocyte remodeling during disease progression, we used biocytin diffusion following single-astrocyte loading to reveal an expanded astrocyte-astrocyte network in Scn1a/- mice long-term, along with increased Cx30 and Cx43 protein levels. An ethidium bromide uptake assay indicated impaired astrocytic hemichannel function in Scn1a/- mice long-term. Regionally, these long-term cellular and network astrocyte modifications coincided with augmented post-tetanic synaptic potentiation. DiscussionIn DS, astrocytes undergo a long-lasting network remodeling. We discuss how this astrocyte remodeling may be related to seizures as well as synaptic and cognitive deficits.

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Genin, A., Janvier, A., Moujellil-Legagneur, T., Blaquiere, M., Chaussy, A., Prive, R., Duprat, F., Mantegazza, M., Audinat, E., Marchi, N., Cresto, N.. 2026-01-06. Long-lasting astrocyte remodeling in Dravet Syndrome Scn1a+/- mouse model.. https://doi.org/10.64898/2026.01.06.697745

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