Abstract:
The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity, especially in its highly condensed form, the perineuronal nets (PNN). In patients with drug-resistant mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis type 1 (HS1) is the most common histopathological finding. This study aimed to evaluate the ECM profile of HS1 in surgically treated drug-resistant patients with MTLE in correlation to clinical findings. Hippocampal sections were immunohistochemically stained for aggrecan, neurocan, versican, chondroitin-sulfate (CS56), fibronectin, Wisteria floribunda agglutinin (WFA), a nuclear neuronal marker (NeuN), parvalbumin (PV), and glial-fibrillary-acidic-protein (GFAP). In HS1, besides the reduced number of neurons and astrogliosis, we found a significantly changed expression pattern of versican, neurocan, aggrecan, WFA-specific glycosylation, and a reduced number of PNNs. Patients with a lower number of epileptic episodes had a less intense diffuse WFA staining in Cornu Ammonis (CA) fields. Our findings suggest that PNN reduction, changed ECM protein, and glycosylation expression pattern in HS1 might be involved in the pathogenesis and persistence of drug-resistant MTLE by contributing to the increase of CA pyramidal neurons\' excitability. This research corroborates the validity of ECM molecules and their modulators as a potential target for the development of new therapeutic approaches to drug-resistant epilepsy.
摘要:
细胞外基质(ECM)是兴奋性和突触可塑性的重要调节因子,尤其是高度浓缩的形式,神经周网(PNN)。在耐药内侧颞叶癫痫(MTLE)患者中,海马硬化1型(HS1)是最常见的组织病理学发现。这项研究旨在评估经手术治疗的MTLE耐药患者中HS1的ECM特征与临床发现的相关性。海马切片对聚集蛋白聚糖进行免疫组织化学染色,Neurocan,versican,硫酸软骨素(CS56),纤连蛋白,紫藤凝集素(WFA),核神经元标记(NeuN),小白蛋白(PV),和胶质纤维酸性蛋白(GFAP)。在HS1中,除了神经元数量减少和星形胶质细胞增生外,我们发现versican的表达模式发生了显著变化,Neurocan,aggrecan,WFA特异性糖基化,和减少数量的PNN。癫痫发作次数较少的患者在CornuAmmonis(CA)田中的弥漫性WFA染色强度较低。我们的研究结果表明,PNN减少,改变ECM蛋白,HS1中的糖基化表达模式可能通过促进CA锥体细胞兴奋性的增加而参与耐药MTLE的发病和持续。这项研究证实了ECM分子及其调节剂作为开发抗药性癫痫新治疗方法的潜在靶标的有效性。