Voltage-gated sodium channels (VGSCs) play pivotal roles in cellular function, particularly in the regulation of electrical signaling. Structural defects in these channels cause deleterious effects in a myriad of cell types, leading to various diseases, like epilepsy, cardiac arrythmias, kidney disease, and certain cancers. Over the past decade, significant efforts have been geared toward developing drugs that target the pore domains of these channels, called pore-blocking agents. This approach has seen several setbacks, commonly due to the lack of isoform-specific binding. Alternative targeting strategies are being used to reduce or eliminate the side effects of pore-blocking agents. Transgenic mouse models have proven useful in such studies, and subtype-selective inhibitors were developed. The zebrafish model system was also used to explore neurological, cardiovascular, and metabolic diseases caused by voltage-gated sodium channel dysfunction. Here, we delve into the growing literature on the structure and function of voltage-gated sodium channels, their role in epilepsy and its comorbidities, and the advancement in the use of zebrafish as a model system to explore these channels as therapeutic targets.

Human subtelomeres contain duplicated sequence that is shared among the ends of non-homologous chromosomes and provides a substrate for ectopic exchange [1–6]. However, incomplete reference assemblies and chromosome-by-chromosome analyses have prevented a population-scale view of the extent and organization of subtelomeric exchange [7–9]. Here we apply a reference-free pangenome approach to 465 near-complete human assemblies, comparing every chromosome end against every other, and find that high-identity pseudo-homolog regions [10] occur on 41 of 48 chromosome arms. These regions group into sequence communities, sets of chromosome ends that share duplicated sequence. Across these communities, copy-number enrichment is concentrated in gene modules associated with chromosome dynamics, intracellular organization and germ-cell development. Human chromosome-contact maps show preferential proximity between subtelomeres with similar sequences, persisting even in adjacent flanks that lack the shared sequence used to define each pair. Mouse contact maps show the same preference, strongest in meiosis at the zygotene bouquet, when telomeres cluster at the nuclear envelope. In a three-generation telomere-to-telomere pedigree, whole-genome comparison identifies putative recombination between subtelomeric regions on non-homologous chromosomes from the same sequence communities, while recovering the obligate X-Y crossover in PAR1, the pseudoautosomal region shared by the X and Y chromosomes, during male meiosis. These results generalize known subtelomeric exchange systems into a near-ubiquitous architecture and support recurrent ectopic exchange as a genome-wide force in the concerted evolution of human chromosome ends.

Background/Objectives: Despite the decades-old ban on lead in fuel, plumbing, consumer goods, industrial processes, and various materials, it remains a public health threat due to its persistent nature. Zebrafish (Danio rerio) are highly effective for modeling several disorders, including those affecting neurological and behavioral functions, and are well-suited for assessing the impact of environmental toxins like lead. This study aimed to investigate the neurodevelopmental effects of embryonic lead exposure using the zebrafish model system. Methods: Embryos were exposed to lead acetate (PbAc) at concentrations ranging from 0.3 to 0.7 µg/mL using an exposure window of 6 to 48 h post-fertilization (hpf). Results: PbAc exposure produced sublethal teratogenic effects in a subset of larvae across concentrations, including tail and spinal deformities, craniofacial abnormalities, and uninflated swim bladder observed at 7 dpf. At 3 days post-fertilization (dpf), spontaneous circle swimming behavior suspected to be seizure-like was observed in the lead-exposed larvae and was more pronounced under light conditions in a dose-dependent manner. Electrophysiological recordings confirmed that larvae exhibiting circle swimming behavior had heightened neural activity, indicating a potential seizure-like phenotype driven by lead exposure. Conclusions: Our findings suggest that embryonic lead exposure leads to morphological defects and seizure susceptibility, demonstrating lead’s neurotoxic potential during early development. Seizure-like behaviors occurred in a non-linear concentration-dependent manner with a photosensitive component, and elevated baseline neural excitability was confirmed by local field potential (LFP) recordings.