2. Academic Validation
  3. Activation of TLR7-mediated autophagy increases epileptic susceptibility via reduced KIF5A-dependent GABAA receptor transport in a murine model

Activation of TLR7-mediated autophagy increases epileptic susceptibility via reduced KIF5A-dependent GABAA receptor transport in a murine model

  • Exp Mol Med. 2023 Jun 1. doi: 10.1038/s12276-023-01000-5.
Jing Liu 1 2,  Pingyang Ke 1,  Haokun Guo 1,  Juan Gu 1,  Yan Liu 1,  Xin Tian 1,  Xuefeng Wang 3,  Fei Xiao 4 5
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, 400016, China.
  • 2 Department of Neurology, Chongqing University Three Gorges Hospital, 165 Xincheng Road, Chongqing, 404100, China.
  • 3 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, 400016, China. xfyp@163.com.
  • 4 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, 400016, China. feixiao81@126.com.
  • 5 Institute for Brain Science and Disease of Chongqing Medical University, Chongqing, 400016, China. feixiao81@126.com.
PMID: 37258573 DOI: 10.1038/s12276-023-01000-5
Abstract

The pathophysiological mechanisms underlying epileptogenesis are poorly understood but are considered to actively involve an imbalance between excitatory and inhibitory synaptic transmission. Excessive activation of Autophagy, a cellular pathway that leads to the removal of proteins, is known to aggravate the disease. Toll-like Receptor (TLR) 7 is an innate immune receptor that regulates Autophagy in infectious and noninfectious diseases. However, the relationship between TLR7, Autophagy, and synaptic transmission during epileptogenesis remains unclear. We found that TLR7 was activated in neurons in the early stage of epileptogenesis. TLR7 knockout significantly suppressed seizure susceptibility and neuronal excitability. Furthermore, activation of TLR7 induced Autophagy and decreased the expression of Kinesin family member 5 A (KIF5A), which influenced interactions with γ-aminobutyric acid type A receptor (GABAAR)-associated protein and GABAARβ2/3, thus producing abnormal GABAAR-mediated postsynaptic transmission. Our results indicated that TLR7 is an important factor in regulating epileptogenesis, suggesting a possible therapeutic target for epilepsy.

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