Variant ‐specific in vitro neuronal network phenotypes and drug sensitivity in SCN2A developmental and epileptic encephalopathy

This study aims to assess the impact of GoF and LoFSCN2A variants on cultured neuronal network activity and explore their modulation by selected antiseizure medications (ASM). To this end, primary cortical cultures were generated from two knock-in mouse lines carrying variants corresponding to human GoFSCN2A p.R1882Q and LoF p.R853Q DEE variant. In  vitro neuronal network activity and responses to ASM were analyzed using multielectrode array (MEA) between 2 and 4 weeks in culture. TheSCN2A p.R1882Q neuronal cultures showed significantly greater mean firing and burst firing. Their network synchronicity was also higher. In contrast, theSCN2A p.R853Q cultures showed lower mean firing rate, and burst firing events were less frequent. The network synchronicity was also lower. Phenytoin and levetiracetam reduced the excitability of GoF cultures, while retigabine showed differential and potentially beneficial effects on cultures with both GoF and LoF variants. We conclude that in  vitro neuronal networks harboringSCN2A GoF or LoF DEE variants present with distinctive phenotypes and responses to ASM.
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research