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Wuttke, T. V.

Publications and source records attributed to Wuttke, T. V..

2 recordsLinked to original sources
bioRxiv2021

In vitro effects of S-Licarbazepine as a potential precision therapy on SCN8A variants causing neuropsychiatric disorders

Background and PurposeAmong genetic epilepsies, variants in sodium channel coding genes constitute a major subgroup. Variants in SCN8A, the coding gene for NaV1.6 channels, are characterized by a variety of symptoms including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, and others such as autistic features, ataxia or dystonia. Standard anticonvulsant treatment has only limited impact on the course of disease. Experimental ApproachPersonalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome intractability. Toward this aim, we investigated in vitro in neuroblastoma cells the effects of S-Licarbazepine, a third-generation dibenzazepine and enhancer of slow inactivation of voltage gated sodium channels, on three gain-of-function NaV1.6 variants linked to representative phenotypes of mild epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D). Key ResultsS-Licarbazepine strongly enhances the slow and - less pronounced - the fast inactivation of NaV1.6 wildtype channels. It acts similarly on all tested variants and irrespective of their particular biophysical dysfunction mechanism. Beyond that S-Licarbazepine has variant-specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D, M1760I) and a trend to reduce the enhanced persistent Na+ current by A1622D variant channels. Conclusion and ImplicationsThese data bring out that S-Licarbazepine not only owns substance-specific effects, but also holds variant-specific effects, which can variably contribute to functional compensation of distinct channel-specific biophysical properties and thereby highlighting the role of personalized approaches, which likely will be key to improved and successful treatment not only of SCN8A-related disease. Bullet pointsO_LIWhat is already known? S-Lic strongly modulates slow and - to a less extend - fast inactivation of wild-type NaV1.6 channels. C_LIO_LIWhat this study adds? Differential modulatory effects of S-Lic extend to NaV1.6 A1622D, M1760I and G1475R variant channels irrespective of their leading biophysical mode of gain-of-function and variably contribute to variant-specific functional compensation of their altered biophysical properties. C_LIO_LIClinical significance: These data suggest therapeutic potential of S-Lic for SCN8A neuropsychiatric disorders and highlight the role of personalized approaches aimed at increasingly precise correction of underlying pathophysiological mechanisms. C_LI

pharmacology and toxicology↗
bioRxiv2021

Dravet variant SCN1AA1783V impairs interneuron firing predominantly by altered channel activation

Dravet syndrome (DS) is a developmental epileptic encephalopathy mainly caused by functional NaV1.1 haploinsufficiency in interneurons (IN). Recently, a new conditional mouse model expressing the recurrent human p.A1783V missense variant has become available. Here we provide an electrophysiological characterization of this variant in tsA201 cells, revealing both altered voltage-dependence of activation and slow inactivation without reduced sodium peak current density. Simulating IN excitability in a Hodgkin-Huxley one-compartment model suggested surprisingly similar firing deficits for Scn1aA1783V and full haploinsufficiency as caused by heterozygous truncation variants. Impaired NaVA1783V channel activation was predicted to have a significantly larger impact on channel function than altered slow inactivation and is therefore proposed as the main mechanism underlying IN dysfunction. The computational model was validated in cortical organotypic slice cultures derived from conditional Scn1aA1783V mice. Pan-neuronal activation of the p.A1783V variant in vitro confirmed the predicted IN firing deficit while demonstrating normal excitability of pyramidal neurons. Taken together these data demonstrate that despite maintained physiological peak currents density LOF gating properties may match effects of full haploinsufficiency on neuronal level, thereby causing DS. HighlightsNaV1.1A1783V alters voltage-dependence of activation and slow inactivation while not affecting fast inactivation. Depolarizing and hyperpolarizing shifts of activation and slow inactivation curves result in combined channel loss of function (LOF). Simulations of NaV1.1A1783V interneuronal properties indicate reduced action potential firing rates comparable to full SCN1A haploinsufficiency, which is often found in Dravet syndrome. In silico modelling identifies impaired channel activation as the predominant mechanism of channel LOF. Panneuronal induction of Scn1a+/A1783V in a cortical slice culture model confirms restriction of loss of function and its restriction to interneurons.

neuroscience↗