Transcriptionally downregulated GABAergic genes associated with synaptic density network dysfunction in temporal lobe epilepsy.

Abstract

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. 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. 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. 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.