Microglial Displacement of GABAergic Synapses Is a Protective Event during Complex Febrile Seizures
Yushan Wan,
Bo Feng,
Yi You,
Jie Yu,
Cenglin Xu,
Haibin Dai,
Bruce D. Trapp,
Peng Shi,
Zhong Chen,
Weiwei Hu
Affiliations
Yushan Wan
Department of Pharmacology and Department of Pharmacy of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, People’s Republic of China
Bo Feng
Department of Pharmacology and Department of Pharmacy of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, People’s Republic of China
Yi You
Department of Pharmacology and Department of Pharmacy of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, People’s Republic of China
Jie Yu
Laboratory of Brain Function and Disease in Chinese Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
Cenglin Xu
Department of Pharmacology and Department of Pharmacy of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, People’s Republic of China
Haibin Dai
Department of Pharmacology and Department of Pharmacy of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, People’s Republic of China
Bruce D. Trapp
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Peng Shi
Department of Pharmacology and Department of Pharmacy of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, People’s Republic of China
Zhong Chen
Department of Pharmacology and Department of Pharmacy of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, People’s Republic of China; Laboratory of Brain Function and Disease in Chinese Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China; Epilepsy Center, Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Corresponding author
Weiwei Hu
Department of Pharmacology and Department of Pharmacy of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, People’s Republic of China; Corresponding author
Summary: Complex febrile seizures (FSs) lead to a high risk of intractable temporal lobe epilepsy during adulthood, yet the pathological process of complex FSs is largely unknown. Here, we demonstrate that activated microglia extensively associated with glutamatergic neuronal soma displace surrounding GABAergic presynapses in complex FSs. Patch-clamp electrophysiology establishes that the microglial displacement of GABAergic presynapses abrogates a complex-FS-induced increase in GABAergic neurotransmission and neuronal excitability, whereas GABA exerts an excitatory action in this immature stage. Pharmacological inhibition of microglial displacement of GABAergic presynapses or selective ablation of microglia in CD11bDTR mice promotes the generation of complex FSs. Blocking or deleting the P2Y12 receptor (P2Y12R) reduces microglial displacement of GABAergic presynapses and shortens the latency of complex FSs. Together, microglial displacement of GABAergic presynapses, regulated by P2Y12R, reduces neuronal excitability to mitigate the generation of complex FSs. Microglial displacement is a protective event during the pathological process of complex FSs.
