GABA tonic currents and glial cells are altered during epileptogenesis in a mouse model of Dravet syndrome

Abstract

Dravet Syndrome (DS) is a rare autosomic encephalopathy with epilepsy linked to Nav1.1 channel mutations and defective GABAergic signaling. Effective therapies for this syndrome are lacking, urging a better comprehension of the mechanisms involved. In a recognized mouse model of DS, we studied GABA tonic current, a form of inhibition largely neglected in DS, in brain slices from developing mice before spontaneous seizures are reported. In neurons from the temporal cortex (TeCx) and CA1 region, GABA tonic current was reduced in DS mice compared to controls, while in the entorhinal cortex (ECx) it was not affected. In this region however allopregnanonole potentiation of GABA tonic current was reduced in DS mice, suggesting altered extrasynaptic GABAA subunits. Using THIP as a selective agonist, we found reduced δ subunit mediated tonic currents in ECx of DS mice. Unexpectedly in the dentate gyrus (DG), a region with high δ subunit expression, THIP-evoked currents in DS mice were larger than in controls. An immunofluorescence study confirmed that δ subunit expression was reduced in ECx and increased in DG of DS mice. Finally, considering the importance of neuroinflammation in epilepsy and neurodevelopmental disorders, we evaluated classical markers of glia activation. Our results show that DS mice have increased Iba1 reactivity and GFAP expression in both ECx and DG, compared to controls. Altogether we report that before spontaneous seizures, DS mice develop significant alterations of GABA tonic currents and glial cell activation. Understanding all the mechanisms involved in these alterations during disease maturation and progression may unveil new therapeutic targets.

Astrocytes as a target for therapeutic strategies in epilepsy: current insights

“…Studies in experimental models of TLE reported that GABA released by reactive astrocytes from Bestrophin-1 channels strongly contributes to the compensatory shift of E/I balance in epileptic hippocampi. The tonic release of GABA from astrocytes is one of the key mechanisms by which astrocytes control epileptic seizures ( Crunelli et al, 2011 ; Muller et al, 2020 ; Goisis et al, 2022 ). By modulating tonic GABA release from astrocytes, it might be possible to target epileptic seizures and other neurological disorders ( Muller et al, 2020 ; Pandit et al, 2020 ).…”

“…Dravet syndrome (DS)or myoclonic epilepsy in infancy (MEI) is a rare, genetic epileptic encephalopathy which is linked to de novo loss of function mutations of the SCNA1 gene encoding for the α subunit of Nav1.1 voltage-dependent sodium channels ( Claes et al, 2001 ). In experimental models of DS, during the development of seizures, changes in GABA A extrasynaptic receptor composition and GABA tonic currents have been recently shown to occur in parallel with an increase in microglia and astrocyte reactivity ( Satta et al, 2021 ; Goisis et al, 2022 ). Moreover, GAT-1 is expressed in the nerve endings of GABAergic interneurons and astrocytes.…”

From synapses to circuits: What mouse models have taught us about how autism spectrum disorder impacts hippocampal function

“…In SCN1A haplodeficient (-/+) mice, a Dravet syndrome model, one recent study reported increased GFAP expression and an increased number of Iba1-positive microglia in DG, implying increased reactivity of astrocytes and microglia (Goisis et al, 2022). Additionally, this study reported a reduction in tonic GABA current in CA1 pyramidal neurons, which needs further investigation due to its inconsistency with existing evidence showing the positive correlation between astrocytic reactivity and tonic GABA current (Goisis et al, 2022). In SCN2A-deficient mice, another study reported partially activated microglia, evidenced by increased cell bodies and reduced branches (Yang et al, 2023).…”

Insulin decreases epileptiform activity in rat layer 5/6 prefrontal cortex in vitro

“…In recent work, by using a kindling model of epilepsy in the hippocampus, it was demonstrated that Zn 2+ decreases the antiseizure effects of ganaxolone by selectively blocking the extrasynaptic δ GABA A receptors (Chuang & Reddy, 2019). Also, it was reported that epilepsy associated with a mouse model of Dravet syndrome, involves a reduction of δ subunit mediated tonic currents in the entorhinal cortex and CA1 hippocampal neurons (Goisis et al., 2022). Previously, we have found that insulin (25–500 nM) increased inhibitory tonic currents mediated by α5 an δ subunit‐containing GABA A receptors in the prefrontal cortex (PFC).…”