Biology subjects

Adney, S. K.

Publications and source records attributed to Adney, S. K..

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↗

bioRxiv2026

Excitatory Dysfunction and Phenotypic Rescue in a Human Neuronal Model of SCN2A-Related Disorders

SCN2A-related disorders result from pathogenic variants in the gene encoding for the voltage-gated sodium channel Nav1.2. Collectively, these disorders result in variable age of onset epilepsy, autism spectrum disorder, and epileptic encephalopathies. While the mechanisms of haploinsufficiency resulting in autism spectrum disorder have been explored in detail, few studies report the impact of pathogenic missense variants in human neurons. In this work, we combined conventional electrophysiology and high-throughput all-optical electrophysiology assays to analyze the SCN2A p.M1879T pathogenic variant associated with early-onset epilepsy and developmental delay. In both platforms, iPSC-derived excitatory neurons expressing the disease variant showed greater firing at higher stimuli compared to the isogenic control neurons (corrected by CRISPR/Cas9), as well as changes to action potential shape (steeper slope and larger amplitude) with evoked firing. We used machine learning techniques on the optical physiology dataset to classify the two genotypes, finding that sodium channel blocking anti-seizure drugs could restore an isogenic phenotype. This work demonstrates proof of sodium channel blocker efficacy in a human neuronal model of SCN2A-related epilepsy and highlights the power of leveraging high-throughput all-optical electrophysiology for testing drug efficacy.

neuroscience↗

bioRxiv2020

Functional and Pharmacological Evaluation of a Novel SCN2A Variant Linked to Early-onset Epilepsy

ObjectiveWe identified a novel de novo SCN2A variant (M1879T) associated with infantile-onset epilepsy that responded dramatically to sodium channel blocker antiepileptic drugs. We analyzed the functional and pharmacological consequences of this variant to establish pathogenicity, and to correlate genotype with phenotype and clinical drug response. MethodsThe clinical and genetic features of an infant boy with epilepsy are presented. We investigated the effect of the variant using heterologously expressed recombinant human NaV1.2 channels. We performed whole-cell patch clamp recording to determine the functional consequences and response to carbamazepine. ResultsThe M1879T variant caused disturbances in channel inactivation including substantially depolarized voltage-dependence of inactivation, slower time course of inactivation, and enhanced resurgent current that collectively represent a gain-of-function. Carbamazepine partially normalized the voltage-dependence of inactivation and produced use-dependent block of the variant channel at high pulsing frequencies. Carbamazepine also suppresses resurgent current conducted by M1879T channels, but this effect was explained primarily by reducing the peak transient current. Molecular modeling suggests that the M1879T variant disrupts contacts with nearby residues in the C-terminal domain of the channel. InterpretationOur study demonstrates the value of conducting functional analyses of SCN2A variants of unknown significance to establish pathogenicity and genotype-phenotype correlations. We also show concordance of in vitro pharmacology using heterologous cells with the drug response observed clinically in a case of SCN2A-associated epilepsy.

neuroscience↗