High-Frequency rTMS Improves Cognitive Function by Regulating Synaptic Plasticity in Cerebral Ischemic Rats

Poststroke cognitive impairment (PSCI) is one of the most severe sequelae of stroke and lacks effective treatment. Previous studies have shown that high-frequency repetitive transcranial magnetic stimulation (rTMS) may be a promising PSCI therapeutic approach, but the underlying mechanism is unclear. To uncover the effect of rTMS on PSCI, a transient middle cerebral artery occlusion (tMCAO) model was established. Modified Neurological Severity Score (mNSS) test and Morris Water Maze (MWM) test were performed to assess the neurological and cognitive function of rats. Furthermore, to explore the underlying mechanism, differentially expressed genes (DEGs) in the hippocampus of rats in the rTMS group and tMCAO group were compared using RNA sequencing. Then, bioinformatics analysis, including gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and protein-protein interaction (PPI) network analysis, was conducted to elaborate these DEGs. Our results indicated that high-frequency rTMS could significantly improve neurological and cognitive function, according to mNSS and MWM tests. We found 85 DEGs, including 71 upregulated genes and 14 downregulated genes, between the rTMS group and tMCAO group. The major functional category was related to chemical synaptic transmission modulation and several DEGs were significantly upregulated in processes related to synaptic plasticity, such as glutamatergic synapses. Calb2, Zic1, Kcnk9, and Grin3a were notable in PPI analysis. These results demonstrate that rTMS has a beneficial effect on PSCI, and its mechanism may be related to the regulation of synaptic plasticity and functional genes such as Calb2, Zic1, Kcnk9, and Grin3a in the hippocampus.

卒中后认知障碍（PSCI）是卒中最严重的后遗症之一，且缺乏有效的治疗方法。先前的研究表明，高频重复经颅磁刺激（rTMS）可能是一种有前景的PSCI治疗方法，但其潜在机制尚不清楚。为了揭示rTMS对PSCI的影响，建立了大脑中动脉短暂闭塞（tMCAO）模型。采用改良神经功能缺损评分（mNSS）测试和莫里斯水迷宫（MWM）测试来评估大鼠的神经和认知功能。此外，为了探索潜在机制，利用RNA测序比较了rTMS组和tMCAO组大鼠海马中的差异表达基因（DEGs）。然后，进行了生物信息学分析，包括基因本体论（GO）分析、京都基因与基因组百科全书（KEGG）分析和蛋白质 - 蛋白质相互作用（PPI）网络分析，以阐述这些DEGs。我们的结果表明，根据mNSS和MWM测试，高频rTMS能够显著改善神经和认知功能。我们在rTMS组和tMCAO组之间发现了85个DEGs，其中包括71个上调基因和14个下调基因。主要功能类别与化学突触传递调节有关，并且在与突触可塑性相关的过程中，如谷氨酸能突触，几个DEGs显著上调。在PPI分析中，Calb2、Zic1、Kcnk9和Grin3a较为显著。这些结果表明，rTMS对PSCI具有有益作用，其机制可能与海马中突触可塑性以及Calb2、Zic1、Kcnk9和Grin3a等功能基因的调节有关。