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

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.

Spadin Modulates Astrocytic Passive Conductance via Inhibition of TWIK-1/TREK-1 Heterodimeric Channels

“…Clearly, antidepressant effects have been reported in both TREK-1 KO mice and mice treated with spadin, a specific TREK-1 inhibitor [ 23 , 53 ]. Recently, we also reported specific KD of TREK-1 in the hippocampal neurons revealed antidepressant effects [ 54 ], suggesting that inhibition of TREK-1 in neurons is important for antidepressant phenotypes. However, in the present study, we clearly demonstrated that astrocytic TREK-1 is critical for passive conductance, and spadin, a potent antidepressant drug, can efficiently inhibit astrocytic passive conductance.…”

Contribution of Neuronal and Glial Two-Pore-Domain Potassium Channels in Health and Neurological Disorders

“…Both spadin and SID1900 enhanced the excitability of serotonergic neurons in mice, alleviating depressive symptoms [57,58]. TREK-1 knockdown in hippocampal neurons alleviated depressive symptoms in a mouse model of lipopolysaccharideinduced depression [61]. Consistent with the studies on rodent models, four single nucleotide polymorphisms in TREK-1 were also identified in some patients with treatment resistance in major depressive disorders [62] These observations suggest that TREK-1 may be a useful therapeutic target in depression.…”

Negative Influence by the Force: Mechanically Induced Hyperpolarization via K2P Background Potassium Channels

“…While TREK/TRAAK mechanosensitivity is clearly important in some tissues (see below), elsewhere, the mechanical stimulation appears to be less probable and the channels are mainly controlled by other regulatory factors. The members of the TREK subfamily are abundantly expressed at several locations (e.g., widespread expression in the neurons of the different brain regions [50][51][52][53][54], or high TREK-1 expression in the human adrenal gland [55,56]), where it is far from certain whether, or how, the cellular responsiveness to mechanical stimuli contributes to the physiological function.…”