Long-lasting remodeling of astrocytes in an Scna1+/- mouse model of Dravet syndrome.

OBJECTIVE

Dravet syndrome (DS) is a prototypical developmental and epileptic encephalopathy caused by mutations in the SCN1A gene, leading to loss of function of the voltage-gated sodium channel Naᵥ1.1. 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.

METHODS

Using a heterozygous Scn1a knockout (Scn1a+/-) mouse model that recapitulates the DS-human phenotype, we examined astrocyte remodeling at landmark disease stages, as defined by video-electroencephalography and behavioral readouts.

RESULTS

From initial disease aggravation (postnatal day [PN] 20-35) to long-term stabilization (up to PN90), Scn1a+/- mice showed increased hippocampal and cortical glial fibrillary acidic protein (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. Importantly, these disease-stage-dependent astrocyte modifications were not associated with macroscopic hippocampal sclerosis or cortical atrophy. To further study astrocyte remodeling, we used biocytin diffusion following single-astrocyte loading to reveal an expanded astrocyte-astrocyte network in Scn1a+/- mice long-term, along with increased connexin (Cx30 and Cx43) protein levels. An ethidium bromide uptake assay indicated impaired astrocytic hemichannel function in Scn1a+/- mice. Regionally, these long-term cellular and network astrocyte modifications coincided with augmented posttetanic synaptic potentiation.

SIGNIFICANCE: In DS, astrocytes undergo long-term remodeling independent of tissue damage. We discuss the association between astrocyte network changes and seizures, as well as synaptic and cognitive deficits.