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

Figures

• 

  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).