Li Melody, Eltabbal Mohamed, Tran Hoang-Dai, Kuhn Bernd
Optical Neuroimaging Unit, Okinawa Institute of Science and Technology Graduate University (OIST), 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan.
iScience. 2023 Oct 5;26(11):108138. doi: 10.1016/j.isci.2023.108138. eCollection 2023 Nov 17.
SCN2A protein-truncating variants (PTV) can result in neurological disorders such as autism spectrum disorder and intellectual disability, but they are less likely to cause epilepsy in comparison to missense variants. While studies showed PTV reduce action potential firing, consequences at network level remain elusive. Here, we generated a mouse model of Scn2a insufficiency using antisense oligonucleotides (Scn2a ASO mice), which recapitulated key clinical feature of SCN2A PTV disorders. Simultaneous two-photon Ca imaging and electrocorticography (ECoG) in awake mice showed that spontaneous Ca transients in somatosensory cortical neurons, as well as their pairwise co-activities were generally decreased in Scn2a ASO mice during spontaneous awake state and induced seizure state. The reduction of neuronal activities and paired co-activity are mechanisms associated with motor, social and cognitive deficits observed in our mouse model of severe Scn2a insufficiency, indicating these are likely mechanisms driving SCN2A PTV pathology.
SCN2A蛋白截短变异（PTV）可导致神经疾病，如自闭症谱系障碍和智力残疾，但与错义变异相比，它们引发癫痫的可能性较小。虽然研究表明PTV会减少动作电位发放，但在网络层面的后果仍不明确。在此，我们使用反义寡核苷酸构建了Scn2a功能不足的小鼠模型（Scn2a ASO小鼠），该模型概括了SCN2A PTV疾病的关键临床特征。对清醒小鼠同时进行双光子钙成像和皮质电图（ECoG）检测发现，在自发清醒状态和诱发癫痫状态下，Scn2a ASO小鼠体感皮质神经元的自发钙瞬变及其成对协同活动普遍减少。神经元活动和成对协同活动的减少是我们在严重Scn2a功能不足小鼠模型中观察到的运动、社交和认知缺陷相关机制，表明这些可能是驱动SCN2A PTV病理的机制。
