Erbin Regulates Neuronal Hyperexcitability and Seizure Susceptibility in Temporal Lobe Epilepsy
Shenglin Wang1,3 · Yuping Zhao2,3,4 · Yuansong Zhang2,3,4 · Yaling Li2 · Yiru Zhang5 · Yangxi Chen6 · Xin Xu1,3 · Guohui Jiang7 · Hui Zhang2,3,4 · Haiqing Zhang8 · Xuefeng Wang1,3 · Xiujuan Mi9,10 · Min Yang2,3,4 · Yixue Gu1,3
1 Department of Neurology, Chongqing Key Laboratory of Major Neurological and Mental Disorders, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
2 Department of Geriatrics, Laboratory of Research and Translation for Geriatric Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
3 Department of Epilepsy Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
4 Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing 400016, China
5 The First Clinical Medical College, Chongqing Medical University, Chongqing 400016, China
6 CQMU‑University of Leicester Joint Institute, Chongqing Medical University, Chongqing 400016, China
7 The Neurology Department and Neurological Disease Research Institute of the Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Nanchong, Sichuan 637000, China
8 Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou, China
9 Department of Encephalopathy, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, China
10 Department of Encephalopathy, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing 400021, China
Abstract
Temporal lobe epilepsy (TLE) is a common intractable form of epilepsy, but the underlying mechanisms remain elusive. Here, we report the upregulation of the postsynaptic scaffolding protein Erbin in epileptic foci from human patients with TLE and in a pilocarpine-induced mouse model. We subsequently modulated Erbin levels in vivo after status epilepticus. Erbin knockdown resulted in less frequent and shorter spontaneous recurrent seizures, whereas Erbin overexpression exacerbated them. Erbin modulation also produced significant changes in neuronal excitability, including action potentials, miniature excitatory postsynaptic currents, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated currents. Furthermore, Erbin knockdown decreased dendritic spine density and the density of excitatory synapses in the dentate gyrus inner molecular layer, whereas Erbin overexpression increased the density of excitatory synapses. Overall, we provide the first evidence that Erbin is upregulated in TLE and exerts a proepileptic effect by controlling synaptic function and structure, identifying it as a promising therapeutic target.
Keywords
Temporal lobe epilepsy; Erbin; Dendritic spines; Neuronal hyperexcitability; Seizure susceptibility
