The potential role of the HCN1 ion channel and BDNF-mTOR signaling pathways and synaptic transmission in the alleviation of PTSD

Lianghui Ni,Changjiang Li,Hong Wang,Hongwei Sun,Sixuan Dong,Yujia Kong,Guohua Lu,Zhongde Du,Yanling Xu,Yanyu Wang,Lin Sun,Qi Li

doi:10.1038/s41398-020-0782-1

Abstract

The function of the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) and the expression of brain-derived neurotrophic factor (BDNF) may be involved in the pathogenesis of post-traumatic stress disorder (PTSD). This study aims to explore the role of the HCN1 channel, BDNF, and mTOR in the actions of PTSD and to examine whether synaptic transmission or plasticity is involved in the regulation of this disease. In the present study, rats were exposed to the single prolonged stress and electric foot shock (SPS&S) procedure, which can induce PTSD-like behaviors in rats. ZD7288 was administered by intracerebroventricular (i.c.v.) injection to one experimental group to inhibit the function of the HCN1 ion channel while 8-Br-cAMP was administered to another group to activate the function of the HCN1 ion channel. A series of behavioral tests and biochemical assessments of certain proteins (HCN1, BDNF, and pmTOR) and synaptic ultrastructure in the prefrontal cortex (PFC) and hippocampus (Hip) were then conducted. The SPS&S procedure induced apparent PTSD-like symptoms in rats. The administration of ZD7288 reduced the immobility time and escape latency time in the forced swim test (FST) and water maze test (WMT) with a decreased level of HCN1, upregulated BDNF-mTOR signaling pathways in the PFC and Hip, and synaptic ultrastructure changes in the PFC. In contrast, the administration of 8-Br-cAMP, which led to a higher level of HCN1 in PFC and Hip, resulted in a decreased number of entries to the open arms without significant change in total arm entries in the elevated plus maze test (EPMT) as well as a shorter center square distance and total distance in the open field test (OFT). Extended escape latency time was also observed in the WMT although there was no alteration of BDNF-mTOR signaling pathways and synaptic ultrastructure in the PFC and Hip. Overall, the inhibition of HCN1, which can alleviate PTSD-like behavior of rats by relieving depression and improving learning ability, may be related to the upregulated BDNF-mTOR signaling pathways and synaptic transmission.

Highlights

Post-traumatic stress disorder (PTSD) is a mental disorder caused by various events that involve threat to the physical integrity of oneself or others
This study explores the role of the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) channel, brain-derived neurotropic factor (BDNF), and mammalian target of rapamycin (mTOR) in the actions of PTSD in order to examine whether synaptic transmission or plasticity is involved in the regulation of this disease
From the results of the Western blot and immunofluorescence assay (Fig. 2a–l), the expression of HCN1, BDNF, and pmTOR in the prefrontal cortex (PFC) and Hip were lower in the single prolonged stress and electric foot shock (SPS&S) group than those in the control group

Summary

Introduction

Post-traumatic stress disorder (PTSD) is a mental disorder caused by various events that involve threat to the physical integrity of oneself or others. HCN1 appears to be the most predominant isoform expressed in the hippocampus (Hip), prefrontal cortex (PFC), neocortex, and cerebellar cortex. It can be regulated by the nucleotide cyclic adenosine 3',5'-monophosphate (cAMP) and ZD72887. We found that the HCN1-related brain-derived neurotropic factor (BDNF) signaling pathways in the PFC are involved in alleviating PTSD-like effects in rats[3]. These findings indicate that HCN1 has a significant effect on the pathogenesis of PTSD, while the definite function of this channel is yet to be known

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