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

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. chenhf@uestc.edu.cn.
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. chenhf@uestc.edu.cn.
⁹ Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. 405035@csu.edu.cn.
¹⁰ Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland. 405035@csu.edu.cn.
¹¹ National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. 405035@csu.edu.cn.
¹² Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. fenglihx@163.com.
¹³ National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. fenglihx@163.com.
¹⁴ Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. hushuo2018@163.com.
¹⁵ National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. hushuo2018@163.com.
¹⁶ Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. hushuo2018@163.com.

^# Contributed equally.

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

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

Rong Li et al. Eur J Nucl Med Mol Imaging. 2025 May.

. 2025 May;52(6):1970-1988.

doi: 10.1007/s00259-024-07054-5. Epub 2025 Jan 8.

Authors

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. chenhf@uestc.edu.cn.
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. chenhf@uestc.edu.cn.
⁹ Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. 405035@csu.edu.cn.
¹⁰ Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland. 405035@csu.edu.cn.
¹¹ National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. 405035@csu.edu.cn.
¹² Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. fenglihx@163.com.
¹³ National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. fenglihx@163.com.
¹⁴ Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. hushuo2018@163.com.
¹⁵ National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. hushuo2018@163.com.
¹⁶ Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. hushuo2018@163.com.

^# 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.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This retrospective study was approved by the Ethics Committee of Central South University. Written informed consent was obtained from all participants prior to enrolment. Consent for publication: Not applicable. Competing interests: Axel Rominger and Kuangyu Shi are editors of the journal European Journal of Nuclear Medicine and Molecular Imaging. The other authors declare that they have no competing interests.

References

1. Stam CJ. Modern network science of neurological disorders. Nat Rev Neurosci. 2014;15:683–95. - PubMed
1. Ryan TJ, Grant SGN. The origin and evolution of synapses. Nat Rev Neurosci. 2009;10:701–12. - PubMed
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1. Staley K. Molecular mechanisms of epilepsy. Nat Neurosci. 2015;18:367–72. - PubMed - PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources