SCN1A/Na_V1.1 channelopathies: Mechanisms in expression systems, animal models, and human iPSC models

Abstract

Summary Pathogenic SCN1A/NaV1.1 mutations cause well‐defined epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and the severe epileptic encephalopathy Dravet syndrome. In addition, they cause a severe form of migraine with aura, familial hemiplegic migraine. Moreover, SCN1A/NaV1.1 variants have been inferred as risk factors in other types of epilepsy. We review here the advancements obtained studying pathologic mechanisms of SCN1A/NaV1.1 mutations with experimental systems. We present results gained with in vitro expression systems, gene‐targeted animal models, and the induced pluripotent stem cell (iPSC) technology, highlighting advantages, limits, and pitfalls for each of these systems. Overall, the results obtained in the last two decades confirm that the initial pathologic mechanism of epileptogenic SCN1A/NaV1.1 mutations is loss‐of‐function of NaV1.1 leading to hypoexcitability of at least some types of γ‐aminobutyric acid (GABA)ergic neurons (including cortical and hippocampal parvalbumin‐positive and somatostatin‐positive ones). Conversely, more limited results point to NaV1.1 gain‐of‐function for familial hemiplegic migraine (FHM) mutations. Behind these relatively simple pathologic mechanisms, an unexpected complexity has been observed, in part generated by technical issues in experimental studies and in part related to intrinsically complex pathophysiologic responses and remodeling, which yet remain to be fully disentangled.

Interneuron Dysfunction in a New Mouse Model of SCN1A GEFS+

“…The present study did not evaluate the properties of the underlying sodium currents. However, studies in heterologous systems have shown that missense mutations located in transmembrane segments can lead to misfolding of the sodium channel assembly ( Rusconi et al, 2007 , 2009 ; Bechi et al, 2015 ; for review, see Terragni et al, 2018 ; Mantegazza and Broccoli, 2019 ). The Scn1a K1270T missense mutation, located in the S2 transmembrane segment of domain DIII, could lead to misfolding of the Nav1.1 channel in a way that alters voltage-dependent gating properties and/or trafficking of the channel, which in turn could contribute to the reduced AP amplitude.…”

Interneuronal dynamics facilitate the initiation of cortical spreading depression

“…One of these mutations (NaV1.1) has also been identified in FHM-3 patients (Tiwari et al, 2020), although its role in migraines and CSD is less clear. In particular, it remains an open question whether the FHM-3 mutation leads to a gain or loss of function of the channel (Hedrich et al, 2014;Mantegazza & Broccoli, 2019). NaV1.1 channels are particularly important for interneuronal excitability, and it is also unclear how changes in this excitability may contribute to initiating CSD.…”

“…More recently, mutations in the sodium channel prevalent in cortical interneurons have been implicated in the initiation of CSD. Specifically, a mutation of the NaV 1.1 sodium channel (SCN1A gene) has been identified as FHM-3 (Dichgans et al, 2005;Mantegazza & Broccoli, 2019;Tiwari et al, 2020). At this point, it is not clear whether this mutation causes a gain or loss of function in the channel (Cestèle et al, 2008(Cestèle et al, , 2013Kahlig et al, 2008;Mantegazza & Broccoli, 2019).…”

“…Specifically, a mutation of the NaV 1.1 sodium channel (SCN1A gene) has been identified as FHM-3 (Dichgans et al, 2005;Mantegazza & Broccoli, 2019;Tiwari et al, 2020). At this point, it is not clear whether this mutation causes a gain or loss of function in the channel (Cestèle et al, 2008(Cestèle et al, , 2013Kahlig et al, 2008;Mantegazza & Broccoli, 2019). In epileptic pathologies, a mutation in the NaV 1.1 channel causes a loss of function in the channel leading to reduced excitation of cortical interneurons, and a subsequent disinhibition and hyperexcitability of the pyramidal cells (Hedrich et al, 2014).…”

“…In epileptic pathologies, a mutation in the NaV 1.1 channel causes a loss of function in the channel leading to reduced excitation of cortical interneurons, and a subsequent disinhibition and hyperexcitability of the pyramidal cells (Hedrich et al, 2014). Conversely, evidence in cell cultures points to a gain of function in the channel, leading to hyperexcitability of the interneurons (Mantegazza & Broccoli, 2019). Despite these conflicting hypotheses regarding the role of the FHM-3 mutation in spike block initiation, it is clear that the interneurons are critical in this process, a notion also supported by computational studies (Desroches et al, 2019).…”