Que Z, Olivero-Acosta MI, Zhang J, Eaton M, Tukker AM, Chen X, Wu J, Xie J, Xiao T, Wettschurack K, Yunis L, Shafer JM, Schaber JA, Rochet J-C, Bowman AB, Yuan C, Huang Z, Hu C-D, Trader DJ, Skarnes WC, Yang Y.
Journal of Neuroscience, 2021
Scientists explore underlying mechanisms of epilepsy variant and reveal potential new therapeutic target
The L1342P variant of the SCN2A gene has been identified as a cause of pediatric epilepsy, but scientists do not fully understand the mechanism underlying L1342P-mediated seizures or the pharmacogenetics of the variant. Experiments using cortical neurons derived from human induced pluripotent stem cells (hiPSCs) carrying the epilepsy-associated sodium channel Nav1.2-L1342P genetic variant demonstrated increased intrinsic excitability, higher sodium current density, and enhanced bursting and network firing—findings that mimic the hyperexcitability of neurons seen in humans affected by epilepsy.
To explore spontaneous neuronal network activity label-free and in real time, the authors used Axion’s Maestro multielectrode array (MEA) system to compare neurons carrying the variant with control neurons. In addition to demonstrating elevated network excitability caused by the L1342P variant, the MEA analysis also showed that neurons carrying the variant are likely to have a reduced sensitivity to phenytoin but are responsive to phrixotoxin-3. Taken together with other findings, the study is an important step towards an understanding of the L1342P epilepsy variant and may lead to personalized phenotyping and drug discovery in the future.