Voltage-Gated Ion Channel Compensatory Effect in DEE: Implications for Future Therapies

Abstract

Developmental and Epileptic Encephalopathies (DEEs) represent a clinically and genetically heterogeneous group of rare and severe epilepsies. DEEs commonly begin early in infancy with frequent seizures of various types associated with intellectual disability and leading to a neurodevelopmental delay or regression. Disease-causing genomic variants have been identified in numerous genes and are implicated in over 100 types of DEEs. In this context, genes encoding voltage-gated ion channels (VGCs) play a significant role, and part of the large phenotypic variability observed in DEE patients carrying VGC mutations could be explained by the presence of genetic modifier alleles that can compensate for these mutations. This review will focus on the current knowledge of the compensatory effect of DEE-associated voltage-gated ion channels and their therapeutic implications in DEE. We will enter into detailed considerations regarding the sodium channels SCN1A, SCN2A, and SCN8A; the potassium channels KCNA1, KCNQ2, and KCNT1; and the calcium channels CACNA1A and CACNA1G.

Keywords: Developmental and Epileptic Encephalopathy (DEE); compensatory effect; ion channels.

Figure 1

Expression profile of the selected VGCs throughout the human lifespan. Among the sodium channels, the expression of (A) SCN1A is lowest prenatally, while the expression of (B) SCN8A and (C) SCN2A is slightly higher, followed by a rise in all three channels expression towards adulthood. Among potassium channels, (D) KCNA1 and (E) KCNT1 show a lower level of expression during early development and increase as development progresses. On the contrary, (F) KCNQ2 shows the highest expression prenatally, followed by a slight decrease postnatally. (G) CACNA1A has a higher postnatal expression, with the highest level in the cerebellar cortex. (H) CACNA1G shows fluctuation within the brain regions, with the highest expression in the cerebellar cortex. Nine windows (W) include fatal development (W1 to W4), birth (W5), infancy and childhood (W6 to W7), adolescence, and adulthood (W8 to W9) in different regions of the brain, including the neocortex (NCX), hippocampus (HIP), amygdala (AMY), striatum (STR), mediodorsal nucleus of the thalamus (MD), and cerebellar cortex (CBC). The graphs are extracted from the PsychNode dataset; Li et al., 2018 (PsychEncode) [61].

Figure 2

Differential expression profile of the selected voltage-gated ion channels in inhibitory (PV, SST, VIP) vs excitatory (EXC) neurons in adult mice cortex. (A) Scn1a, (B) Kcnt1, and (C) Cacna1g show enrichment in inhibitory neurons, whereas (D) Scn2a, (E) Scn8a, (F) Kcnq2, (G) Kcn1a, and (H) Cacna1a display higher enrichment in excitatory neurons (all the graphs extracted from http://research-pub.gene.com/NeuronSubtypeTranscriptomes (accessed on 8 September 2024); Huntley et al., 2020 [91]).

Figure 3

Model of the compensatory effect of certain VGCs in Dravet syndrome. (A) Enrichment pattern of selected voltage-gated ion channels in excitatory neurons (EN) and inhibitory neurons (IN) in healthy conditions. (B) SCN1A LOF in Dravet syndrome causes hypo-excitability in inhibitory neurons, leading to hyper-excitability of excitatory neurons. (C) Manipulating the excitation/inhibition (E/I) ratio by targeting different genes in Dravet syndrome. Inhibiting KCNT1 (Scenario 1), SCN8A (Scenario 2), and CACNA1G (Scenario 3) improves the seizure phenotype, probably by bringing the E/I ratio closer to its optimal level. In contrast, inducing SCN2A (Scenario 4), KCNQ2 (Scenario 5), and CACNA1A (Scenario 6) worsens the phenotype due to increased excitability in an already hyperexcitable network. Sodium, potassium, and calcium channels are shown in orange, purple, and green, respectively. PV, SST, and VIP show inhibitory neurons, and EN refers to excitatory neurons. The model is generated using BioRender (BioRender: Scientific Image and Illustration Software, www.biorender.com).