Purpose

Temporal lobe epilepsy (TLE) is a brain network disorder closely associated with synaptic loss and has a genetic basis. However, the in vivo whole-brain synaptic changes at the network-level and the underlying gene expression patterns in patients with TLE remain unclear.

Methods

In this study, we utilized a positron emission tomography with the synaptic vesicle glycoprotein 2 A radioligand [¹⁸F]SynVesT-1 cohort and two independent transcriptome datasets to investigate the topological properties of the synaptic density similarity network (SDSN) in TLE and its correlation with significantly dysregulated risk genes.

Results

We observed an overall decrease in strength, reduced clustering coefficient, and increased path length of SDSN in TLE, suggesting a loss of connectivity that is accompanied by network reorganization. These changes were predominantly distributed in the temporo-limbic circuit and fronto-parietal networks. Moreover, connectivity changes in SDSN were found to be spatially correlated with the brain-wide expression of TLE risk genes, and the transcriptional correlate of SDSN changes showed a significant relationship with gene dysregulation. In particular, we identified a total of 183 downregulated genes that were functionally enriched for synaptic transmission pathways, forming a highly connected genetic interaction network. Within this set of genes, GABAergic genes such as RBFOX1 play a central role.

Discussion

Our study provides the first evidence that the spatial expression patterns of downregulated risk genes underlie in vivo synaptic density network dysfunction in TLE. These imaging-transcriptomic findings have the potential to guide the development of molecular and genetic network-based therapeutic approaches for TLE.

中文翻译：

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转录下调与颞叶癫痫突触密度网络功能障碍相关的 GABA 能基因

 目的

颞叶癫痫 （TLE） 是一种与突触丢失密切相关的脑网络疾病，具有遗传基础。然而，TLE 患者网络水平的体内全脑突触变化和潜在的基因表达模式仍不清楚。

 方法

在这项研究中，我们利用突触小泡糖蛋白 2 A 放射性配体 [¹⁸F]SynVesT-1 队列和两个独立的转录组数据集的正电子发射断层扫描来研究 TLE 中突触密度相似网络 （SDSN） 的拓扑特性及其与显着失调风险基因的相关性。

 结果

我们观察到 TLE 中 SDSN 的强度总体降低、聚集系数降低和路径长度增加，这表明连接性丢失伴随着网络重组。这些变化主要分布在颞-边缘回路和额顶叶网络中。此外，发现 SDSN 的连接变化与 TLE 风险基因的全脑表达在空间上相关，SDSN 变化的转录相关性与基因失调呈显着关系。特别是，我们总共鉴定了 183 个下调基因，这些基因在突触传递途径中功能丰富，形成了一个高度连接的遗传相互作用网络。在这组基因中，RBFOX1 等 GABA 能基因起着核心作用。

 讨论

我们的研究提供了第一个证据，证明下调风险基因的空间表达模式是 TLE 体内突触密度网络功能障碍的基础。这些成像转录组学发现有可能指导基于分子和遗传网络的 TLE 治疗方法的开发。