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

Rong Li; Ling Xiao; Honghao Han; Hongyu Long; Wei Liao; Zhenzhe Yang; Haoyue Zhu; Xuyang Wang; Ting Zou; Yongwen Huang; Bharat B Biswal; Ming Zhou; Jian Li; Yulai Li; Axel Rominger; Kuangyu Shi; Huafu Chen; Yongxiang Tang; Li Feng; Shuo Hu

doi:10.1007/s00259-024-07054-5

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

Eur J Nucl Med Mol Imaging. 2025 Jan 8. doi: 10.1007/s00259-024-07054-5. Online ahead of print.

Authors

Rong Li^#^{1

2}, Ling Xiao^#³, Honghao Han^#^{1

2}, Hongyu Long⁴, Wei Liao^{1

2}, Zhenzhe Yang^{1

2}, Haoyue Zhu⁴, Xuyang Wang^{1

2}, Ting Zou^{1

2}, Yongwen Huang^{1

2}, Bharat B Biswal^{1

2}, Ming Zhou³, Jian Li³, Yulai Li³, Axel Rominger⁵, Kuangyu Shi^{5

6}, Huafu Chen^{7

8}, Yongxiang Tang^{9

10

11}, Li Feng^{12

13}, Shuo Hu^{14

15

16}

Affiliations

¹ The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 611731, P.R. China.
² MOE Key Laboratory for Neuroinformation, High-Field Magnetic Resonance Brain Imaging Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu, 611731, P.R. China.
³ Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China.
⁴ Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China.
⁵ Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.
⁶ Department of Informatics, Technische Universität München, Munich, Germany.
⁷ The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 611731, P.R. China. [email protected].
⁸ MOE Key Laboratory for Neuroinformation, High-Field Magnetic Resonance Brain Imaging Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu, 611731, P.R. China. [email protected].
⁹ Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. [email protected].
¹⁰ Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland. [email protected].
¹¹ National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. [email protected].
¹² Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. [email protected].
¹³ National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. [email protected].
¹⁴ Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. [email protected].
¹⁵ National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. [email protected].
¹⁶ Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. [email protected].

^# Contributed equally.

PMID: 39777496
DOI: 10.1007/s00259-024-07054-5

Abstract

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.

Keywords: GABAergic inhibition; Gene expression; SV2A PET; Synaptic density network; Temporal lobe epilepsy.

Abstract

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