Biology subjects

Thompson, E. C.

Publications and source records attributed to Thompson, E. C..

3 recordsLinked to original sources

bioRxiv2026

Elevated neuronal excitability and seizure susceptibility in a mouse model of SCN2A-related developmental and epileptic encephalopathy

Pathogenic variants in SCN2A cause a spectrum of neurodevelopmental disorders, including developmental and epileptic encephalopathies (DEE). The patient-associated SCN2A-p.E430A variant selectively shifts voltage-dependence of activation, a mechanism predicted to enhance neuronal excitability. To investigate the functional consequences of the SCN2A-E430A variant, we generated the novel Scn2aE430A mouse model and assessed neuronal excitability, brain activity, seizure susceptibility, and phenytoin responsiveness. Heterozygous Scn2aE430A mice retained normal Scn2a expression levels and did not exhibit premature lethality. Hippocampal pyramidal neurons from heterozygous Scn2aE430A mice were hyperexcitable compared to wild-type neurons. Enhanced long-term potentiation was observed in the CA1 circuit of Scn2aE430A mice. Video-EEG data revealed recurrent epileptiform discharges and spectral abnormalities, but no spontaneous generalized seizure events. In multiple seizure-induction assays, Scn2aE430A mice had no difference in latency to first seizure signs, but exhibited faster seizure generalization and more lethality compared to wild-type mice, indicating alterations in seizure propagation and/or cessation rather than seizure initiation. Pretreatment with phenytoin improved seizure outcomes across all seizure induction methods. Together, these findings demonstrate that selective disruption of Scn2a activation gating is sufficient to drive neuronal hyperexcitability and network dysfunction, establishing the Scn2aE430A mouse as clinically relevant and pharmacologically tractable model of SCN2A-related DEE.

neuroscience↗

bioRxiv2025

Molecular dynamics of the pathogenic KCNQ2 variant G256W reveal mechanisms of channel dysfunction in epileptic encephalopathy

Brain voltage-gated potassium channels containing the subunit KCNQ2 are essential for regulating electrical signals contributing to sensation, learning, memory, and motor control. De novo KCNQ2 variants are among the more common Mendelian causes of early life epilepsy and neurodevelopmental impairment. Some patients with KCNQ2 variants are affected with KCNQ2 developmental and epileptic encephalopathy (KCNQ2 DEE) characterized by seizures and developmental delays. Children with KCNQ2 DEE exhibit a range of impairment patterns that appear to be correlated with specific consequences of the variant for protein function. Here, we used all-atom molecular dynamics to analyze a pathogenic missense variant KCNQ2 G256W, located in the pore turret. G256W subunit simulations showed migration of the hydrophobic W256 sidechain towards the lipid membrane. This movement affected turret structure and mobility prominently involving K255. We identified novel hydrogen bonding interactions in the wild type KCNQ2 turret region which formed a network that extended to the selectivity filter and identified N258, H260P, and K283 as key residues. Simulations comparing WT and G256W tetrameric channels exhibited more conformationally unstable ion selectivity filters for G256W. We analyzed how different stoichiometries of wild type and G256W subunits, as expected in heterozygous individuals, impacted dynamics and compared the G256W results to three additional variants of the turret-selectivity filter network. Our results provide additional support for an integral role of the KCNQ2 turret selectivity filter stability. The majority of severe KCNQ2 DEE variants are clustered near the selectivity filter in the pore domain. Our study provides insights that may be broadly applicable to this clinically important allele subgroup. Broader audience statementA serious childhood illness, called KCNQ2 developmental and epileptic encephalopathy, usually arises from single amino acid substitutions, or missense variants. This paper provides insight into how such a local change can profoundly disrupt the function of a large oligomeric protein containing over 3,400 residues. Molecular dynamics simulations of the pathogenic KCNQ2 pore domain variant, G256W, revealed that W256 changed the structure and flexibility of the pore domain turret and altered the ion selectivity filter. These findings shed light on the functional impact of KCNQ2 pathogenic variants and may help illuminate general mechanisms underlying severe KCNQ2 variants that occur commonly near the ion pore.

neuroscience↗

bioRxiv2024

Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.

neuroscience↗