Patel Dipan C, Swift Nathaniel, Tewari Bhanu P, Browning Jack L, Prim Courtney, Chaunsali Lata, Kimbrough Ian, Olsen Michelle L, Sontheimer Harald
Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA.
Department of Internal Medicine, Gerontology and Geriatric Medicine, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA.
bioRxiv. 2023 May 17:2023.05.16.541066. doi: 10.1101/2023.05.16.541066.
Alterations in the extracellular matrix (ECM) are common in epilepsy, yet whether they are cause or consequence of disease is unknow. Using Theiler's virus infection model of acquired epilepsy we find expression of chondroitin sulfate proteoglycans (CSPGs), a major ECM component, in dentate gyrus (DG) and amygdala exclusively in mice with seizures. Preventing synthesis of CSPGs specifically in DG and amygdala by deletion of major CSPG aggrecan reduced seizure burden. Patch-clamp recordings from dentate granule cells (DGCs) revealed enhanced intrinsic and synaptic excitability in seizing mice that was normalized by aggrecan deletion. experiments suggest that DGCs hyperexcitability results from negatively charged CSPGs increasing stationary cations (K, Ca) on the membrane thereby depolarizing neurons, increasing their intrinsic and synaptic excitability. We show similar changes in CSPGs in pilocarpine-induced epilepsy suggesting enhanced CSPGs in the DG and amygdala may be a common ictogenic factor and novel therapeutic potential.
细胞外基质（ECM）的改变在癫痫中很常见，但它们是疾病的原因还是结果尚不清楚。利用后天性癫痫的泰勒氏病毒感染模型，我们发现硫酸软骨素蛋白聚糖（CSPGs）（一种主要的ECM成分）仅在癫痫发作的小鼠的齿状回（DG）和杏仁核中表达。通过缺失主要的CSPG聚集蛋白聚糖特异性地阻止DG和杏仁核中CSPGs的合成，可减轻癫痫发作负担。来自齿状颗粒细胞（DGCs）的膜片钳记录显示，癫痫发作小鼠的内在和突触兴奋性增强，而聚集蛋白聚糖的缺失可使其恢复正常。实验表明，DGCs的过度兴奋性是由于带负电荷的CSPGs增加了膜上的固定阳离子（K、Ca），从而使神经元去极化，增加其内在和突触兴奋性。我们在毛果芸香碱诱导的癫痫中显示了CSPGs的类似变化，表明DG和杏仁核中CSPGs的增加可能是一个常见的致痫因素和新的治疗潜力。
