The Knockdown of TREK-1 in Hippocampal Neurons Attenuate Lipopolysaccharide-Induced Depressive-Like Behavior in Mice.

Ajung Kim,Hyun-Gug Jung,Seung-Chan Kim,Eun Mi Hwang,Jae-Yong Park,Seok-Geun Lee,Yeong-Eun Kim

doi:10.3390/ijms20235902

Abstract

TWIK-related potassium channel-1 (TREK-1) is broadly expressed in the brain and involved in diverse brain diseases, such as seizures, ischemia, and depression. However, the cell type-specific roles of TREK-1 in the brain are largely unknown. Here, we generated a Cre-dependent TREK-1 knockdown (Cd-TREK-1 KD) transgenic mouse containing a gene cassette for Cre-dependent TREK-1 short hairpin ribonucleic acid to regulate the cell type-specific TREK-1 expression. We confirmed the knockdown of TREK-1 by injecting adeno-associated virus (AAV) expressing Cre into the hippocampus of the mice. To study the role of hippocampal neuronal TREK-1 in a lipopolysaccharide (LPS)-induced depression model, we injected AAV-hSyn-BFP (nCTL group) or AAV-hSyn-BFP-Cre (nCre group) virus into the hippocampus of Cd-TREK-1 KD mice. Interestingly, the immobility in the tail suspension test after LPS treatment did not change in the nCre group. Additionally, some neurotrophic factors (BDNF, VEGF, and IGF-1) significantly increased more in the nCre group compared to the nCTL group after LPS treatment, but there was no difference in the expression of their receptors. Therefore, our data suggest that TREK-1 in the hippocampal neurons has antidepressant effects, and that Cd-TREK-1 KD mice are a valuable tool to reveal the cell type-specific roles of TREK-1 in the brain.

Highlights

TWIK-related potassium channel-1 (TREK-1) is one of the two-pore-domain potassium (K2P) channels involved in the background leakage of potassium ions, and influences resting membrane potential and cell excitability [1]
We created a transgenic mouse in a short time using the pSico-Red-shTREK-1 sequence, which distinguishes the TREK-1 short hairpin ribonucleic acid (shRNA)-expressing cells by fluorescence, developed in the previous study [32]
We named these mice as Cd-TREK-1 KD mice because they expressed TREK-1 shRNA in a Cre-dependent manner and effectively reduced TREK-1

Summary

Introduction

TWIK-related potassium channel-1 (TREK-1) is one of the two-pore-domain potassium (K2P) channels involved in the background leakage of potassium ions, and influences resting membrane potential and cell excitability [1]. Antidepressant effects have been reported in both TREK-1-deficient mice and mice treated with fluoxetine, curcumin, spadin, SID1900, and TKDC, which are well-known TREK-1 inhibitors [2,4,5,6,7,8]. TREK-1 is known to be well expressed in serotonin neurons and neurons of the prefrontal cortex (PFC) and hippocampus, which are important brain regions associated with the cognitive aspects of depression [9,10,11]. The serotonin hypothesis is still controversial in the studies involving humans with major depressive disorder [12], and several magnetic resonance imaging-based studies have reported reduced neuron volumes in the PFC and hippocampus [13,14]. To better understand the antidepressant effects of TREK-1 channels, identifying the effects of TREK-1 on other neurons, the PFC or hippocampus, is significantly useful

Methods

Results

Conclusion