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

作者：Liu, Jing; Ke, Pingyang; Guo, Haokun; Gu, Juan; Liu, Yan; Tian, Xin; Wang, Xuefeng^*; Xiao, Fei^*

来源：Experimental and Molecular Medicine, 2023, 55(6): 1159-1173.

DOI：10.1038/s12276-023-01000-5

• TOLL-LIKE RECEPTORS
• TEMPORAL-LOBE EPILEPSY
• TRAFFICKING
• MITOPHAGY
• MELATONIN
• SYSTEM

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 gamma-aminobutyric acid type A receptor (GABA(A)R)-associated protein and GABA(A)R beta 2/3, thus producing abnormal GABA(A)R-mediated postsynaptic transmission. Our results indicated that TLR7 is an important factor in regulating epileptogenesis, suggesting a possible therapeutic target for epilepsy. @@@ Epilepsy: a receptor protein that can take a tollStudies using a mouse model of epilepsy implicate a protein inside cells called Toll-like receptor 7 (TLR7) in susceptibility to epileptic seizures, suggesting the protein could be a target for antiepileptic drugs. TLR7 is part of the immune system and is found in the external and internal membranes of some cells, recognizing molecules associated with infection and disease. It can, however, lead to damaging over-reactions, including auto-immune responses. Fei Xiao, Xuefeng Wang, and colleagues at Chongqing Medical University in China detected activation of TLR7 in mouse neurons during the cellular changes that underly a susceptibility to epilepsy. They also identified molecular signaling pathways allowing TLR7 activity to disturb nerve transmission by modulating processes that normally degrade used cell components. TLR7 and related proteins may also be involved in other noninfectious diseases of the central nervous system.

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