1. Academic Validation
  2. Endophilin A1 mediates seizure activity via regulation of AMPARs in a PTZ-kindled epileptic mouse model

Endophilin A1 mediates seizure activity via regulation of AMPARs in a PTZ-kindled epileptic mouse model

  • Exp Neurol. 2018 Jun;304:41-57. doi: 10.1016/j.expneurol.2018.02.014.
Xinyuan Yu 1 Tao Xu 1 Shu Ou 1 Jinxian Yuan 1 Jing Deng 1 Rong Li 1 Juan Yang 1 Xi Liu 1 Qi Li 1 Yangmei Chen 2
Affiliations

Affiliations

  • 1 Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: chenym1997@sina.com.
Abstract

Endophilin A1 is a member of the endophilin A family and is primarily expressed in the central nervous system. Endophilin A1 can mediate neuronal excitability by regulating neuronal synaptic plasticity, which indicates that the protein may be involved in epilepsy. However, to date, its role in epilepsy remains unclear. To explore the role of endophilin A1 in epilepsy, we aimed to investigate the expression patterns of endophilin A1 in patients with temporal lobe epilepsy (TLE) and in a pentylenetetrazole (PTZ)-kindled epileptic mouse model and to conduct behavioral and electrophysiological analyses after lentivirus-mediated knockdown of endophilin A1 in the hippocampus of epileptic mice. This study found that the expression of endophilin A1 was significantly up-regulated in the temporal neocortex of TLE patients and in the hippocampus and adjacent temporal cortex of the PTZ-kindled epileptic mouse model. Behavioral analyses indicated that knockdown of endophilin A1 in the mouse hippocampus increased the latency of the first seizure and reduced the frequency and duration of seizure activity. Whole-cell patch-clamp recordings of pyramidal neurons in the hippocampal CA3 area indicated that knockdown of endophilin A1 in the mouse hippocampus resulted in a reduced frequency of action potentials and decreased amplitudes of miniature excitatory postsynaptic currents (mEPSCs) and evoked AMPA-dependent EPSCs. Moreover, western blotting analysis showed that the surface expression of the AMPAR GluR2 subunit was also decreased after endophilin A1 knockdown, and co-immunoprecipitation indicated an association between endophilin A1 and AMPAR GluR2 in the mouse hippocampus. Further, when AMPARs were activated by CX546, the antiepileptic function of endophilin A1 knockdown was decreased. Based on these results, endophilin A1 plays a critical role in epilepsy, and its suppression in the mouse hippocampus can restrain neuronal excitability and seizure activity via regulating AMPARs.

Keywords

AMPA receptors; Endophilin A1; Hippocampus; Temporal lobe epilepsy.

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