Synaptic vesicle protein 2A regulates mossy fiber sprouting in a drug-resistant epilepsy rat model via laminin α5/integrin β1

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2025-09-04 DOI:10.1016/j.brainresbull.2025.111536

Yongfei Shi , Yi Xu , Yinlin Hu , Langtao Liu , Chen Li , Siyin Ren , Guofeng Wu , Likun Wang

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引用次数: 0

Abstract

Drug-resistant epilepsy (DRE) is frequently characterized by pathological mossy fiber sprouting (MFS), which is a defining indicator of aberrant synaptic remodeling within the hippocampus. Despite extensive investigations of the molecular underpinnings of MFS, they remain only partially elucidated. Synaptic vesicle protein 2 A (SV2A) is a key modulator of neurotransmitter exocytosis that has been associated with epileptogenesis. However, its involvement in structural neural plasticity throughout epileptogenic progression remains unclear. In this study, a pilocarpine-induced rat model of DRE was utilized to evaluate the influence of SV2A on MFS. Immunofluorescence, western blot analysis, and the lentivirus-mediated modulation of SV2A expression revealed that SV2A suppression intensified both MFS and seizure severity. Mechanistically, the results of co-immunoprecipitation combined with mass spectrometry suggested that a deficiency of SV2A could facilitate aberrant axonal sprouting via disruption of the laminin α5 (LAMA5)/integrin β1 (ITGB1) signaling cascade. Subsequent validation confirmed that decreased LAMA5 expression and attenuated ITGB1 activation in SV2A-deficient rats were contributory factors to pathological axonal sprouting. These findings implicate SV2A as a critical determinant of structural plasticity in epileptogenesis and highlight the LAMA5/ITGB1 axis as a promising therapeutic avenue for DRE.

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突触囊泡蛋白2A通过层粘连蛋白α5/整合素β1调控耐药癫痫大鼠苔藓纤维发芽。

耐药癫痫（DRE）通常以病理性苔藓纤维发芽（MFS）为特征，这是海马内异常突触重塑的决定性指标。尽管对MFS的分子基础进行了广泛的研究，但它们仍然只是部分阐明。突触囊泡蛋白2A （SV2A）是神经递质胞吐的关键调节剂，与癫痫发生有关。然而，其在癫痫发生过程中与结构神经可塑性的关系尚不清楚。本研究采用匹罗卡品诱导的大鼠DRE模型，评价SV2A对MFS的影响。免疫荧光、western blot分析和慢病毒介导的SV2A表达调节显示，SV2A抑制加重了MFS和癫痫发作的严重程度。机制上，免疫共沉淀结合质谱分析的结果表明，SV2A的缺乏可能通过破坏层粘连蛋白α5 (LAMA5)/整合素β1 （ITGB1）信号级联而促进轴突异常萌发。随后的验证证实，sv2a缺陷大鼠LAMA5表达降低和ITGB1激活减弱是导致病理性轴突发芽的因素。这些发现暗示SV2A是癫痫发生中结构可塑性的关键决定因素，并强调LAMA5/ITGB1轴是治疗DRE的有希望的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.