Genetic and pharmacological inhibition of two-pore domain potassium channel TREK-1 alters depression-related behaviors and neuronal plasticity in the hippocampus in mice

CNS Neurosci Ther. 2021 Feb;27(2):220-232. doi: 10.1111/cns.13450. Epub 2020 Aug 30.


Introduction: The two-pore domain potassium channel TREK-1 is a member of background K+ channels that are thought to provide baseline regulation of membrane excitability. Recent studies have highlighted the putative role of TREK-1 in the action of antidepressants, and its antagonists might be potentially effective antidepressants. However, the mechanisms underlying the actions of TREK-1 are not yet fully understood.

Methods: The expression of TREK-1 was examined in a mouse model of chronic unpredictable mild stress (CUMS) using immunoblotting. Neuron-specific genetic manipulation of TREK-1 was performed through adeno-associated virus. Behavioral tests were performed to evaluate depression-related behaviors. Electrophysiological recordings were used to evaluate synaptic plasticity. Golgi staining was used to examine neuroplasticity.

Results: TREK-1 expression was increased in the mouse hippocampus after CUMS. Knockdown of TREK-1 in hippocampal neurons significantly attenuated depressive-like behaviors and prevented the decrease of CUMS-induced synaptic proteins in mice. Further examination indicated that neuron-specific knockdown of TREK-1 in the hippocampus prevented stress-induced impairment of glutamatergic synaptic transmission in the CA1 region. Moreover, chronic TREK-1 inhibition protected against CUMS-induced depressive-like behaviors and impairment of synaptogenesis in the hippocampus.

Conclusion: Our results indicate a role for TREK-1 in the modulation of synaptic plasticity in a mouse model of depression. These findings will provide insight into the pathological mechanism of depression and further evidence for a novel target for antidepressant treatment.

Keywords: TREK-1; depression; hippocampus; mice; neuronal plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds / administration & dosage
  • Depression / drug therapy
  • Depression / genetics*
  • Depression / psychology
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Oxazoles / administration & dosage
  • Peptides / administration & dosage
  • Potassium Channels, Tandem Pore Domain / antagonists & inhibitors*
  • Potassium Channels, Tandem Pore Domain / genetics*
  • RNA, Small Interfering / administration & dosage


  • Bridged Bicyclo Compounds
  • Oxazoles
  • Peptides
  • Potassium Channels, Tandem Pore Domain
  • RNA, Small Interfering
  • SID1900
  • potassium channel protein TREK-1
  • spadin peptide