Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate firing of globus pallidus neurons in vivo

Chen, Lei; Xu, Rong; Sun, Fengjiao; Xue, Yan; Hao, Xiao-Meng; Liu, Hongxia; Wang, Hua; Chen, Xinyi; Liu, Ziran; Deng, Wenshuai; Han, Xiaohua; Xie, Junxia; Yung, Wing‐Ho

doi:10.1016/j.mcn.2015.04.001

Cited by 18 publications

(16 citation statements)

References 54 publications

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“…In contrast, 8-Br-cAMP is a cell-permeable cAMP analog that can activate the HCN channel 17 . In our behavioral assays following the delivery of 8-Br-cAMP, more severe anxiety symptoms and weakened spontaneity were detected in the OFT, and the results of the EPMT confirmed anxiety-like behaviors and less exploration in novel environments.…”

Section: Discussionmentioning

confidence: 99%

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

Dong

et al. 2020

Transl Psychiatry

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The function of the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) and the expression of brainderived 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.

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Section: Discussionmentioning

confidence: 99%

“…The drugs were delivered into the right or left lateral ventricle (0.8 mm posterior to bregma, 1.5 mm lateral to midline, 3.5 mm ventral to dura) at the rate of 0.5 µl/min via a 5 µl Hamilton syringe. Following at least 5 days of recovery, the rats were tested for behavior 17 .…”

Section: Experimental Group Design and Drug Deliverymentioning

confidence: 99%

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

Dong

et al. 2020

Transl Psychiatry

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“…According to our previous study (Chen et al, 2015 ), we classified pallidal neurons into three types (i.e., higher frequency without pauses, higher frequency with pauses and low frequency with bursts, Figures 2F–H ). Based on this classification, the proportion of 36.17% high frequency without pauses, 48.94% high frequency with pauses and 14.89% low frequency with bursts were observed within the present 47 pallidal neurons.…”

Section: Resultsmentioning

confidence: 99%

“…The other advantage of the present multibarrel microelectrodes is to apply drugs directly to the neurons recorded. According to our previous studies (Xue et al, 2010 ; Chen et al, 2015 ), extracellular recordings were performed in the globus pallidus of normal urethane (1 g/kg, i.p.) anesthetized rats.…”

Section: Methodsmentioning

confidence: 99%

Adenosine A2A Receptor Modulates the Activity of Globus Pallidus Neurons in Rats

et al. 2017

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The globus pallidus is a central nucleus in the basal ganglia motor control circuit. Morphological studies have revealed the expression of adenosine A2A receptors in the globus pallidus. To determine the modulation of adenosine A2A receptors on the activity of pallidal neurons in both normal and parkinsonian rats, in vivo electrophysiological and behavioral tests were performed in the present study. The extracellular single unit recordings showed that micro-pressure administration of adenosine A2A receptor agonist, CGS21680, regulated the pallidal firing activity. GABAergic neurotransmission was involved in CGS21680-induced modulation of pallidal neurons via a PKA pathway. Furthermore, application of two adenosine A2A receptor antagonists, KW6002 or SCH442416, mainly increased the spontaneous firing of pallidal neurons, suggesting that endogenous adenosine system modulates the activity of pallidal neurons through adenosine A2A receptors. Finally, elevated body swing test (EBST) showed that intrapallidal microinjection of adenosine A2A receptor agonist/antagonist induced ipsilateral/contralateral-biased swing, respectively. In addition, the electrophysiological and behavioral findings also revealed that activation of dopamine D2 receptors by quinpirole strengthened KW6002/SCH442416-induced excitation of pallidal activity. Co-application of quinpirole with KW6002 or SCH442416 alleviated biased swing in hemi-parkinsonian rats. Based on the present findings, we concluded that pallidal adenosine A2A receptors may be potentially useful in the treatment of Parkinson's disease.

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“…HCN channels regulate neuronal plasticity and have the advantage of using both voltage dependent mechanisms as well as cAMP intracellular signaling mechanisms [16]. In the midbrain, these channels control the spontaneous activity of dopaminergic neurons and their dysfunction has been linked to the depletion of dopamine in Parkinson's disease [13,16,26]. In the human genome (hg19), the conserved DNMT1dependent locus identified was 321 bp at a CpG island on exon 8 of the gene.…”

Section: Discussionmentioning

confidence: 99%

The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure

Freeman

Lou

et al. 2020

Epigenetics & Chromatin

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Background: Allele-specific DNA methylation (ASM) describes genomic loci that maintain CpG methylation at only one inherited allele rather than having coordinated methylation across both alleles. The most prominent of these regions are germline ASMs (gASMs) that control the expression of imprinted genes in a parent of origin-dependent manner and are associated with disease. However, our recent report reveals numerous ASMs at non-imprinted genes. These non-germline ASMs are dependent on DNA methyltransferase 1 (DNMT1) and strikingly show the feature of random, switchable monoallelic methylation patterns in the mouse genome. The significance of these ASMs to human health has not been explored. Due to their shared allelicity with gASMs, herein, we propose that non-traditional ASMs are sensitive to exposures in association with human disease. Results:We first explore their conservancy in the human genome. Our data show that our putative non-germline ASMs were in conserved regions of the human genome and located adjacent to genes vital for neuronal development and maturation. We next tested the hypothesized vulnerability of these regions by exposing human embryonic kidney cell HEK293 with the neurotoxicant rotenone for 24 h. Indeed,14 genes adjacent to our identified regions were differentially expressed from RNA-sequencing. We analyzed the base-resolution methylation patterns of the predicted non-germline ASMs at two neurological genes, HCN2 and NEFM, with potential to increase the risk of neurodegeneration. Both regions were significantly hypomethylated in response to rotenone. Conclusions:Our data indicate that non-germline ASMs seem conserved between mouse and human genomes, overlap important regulatory factor binding motifs, and regulate the expression of genes vital to neuronal function. These results support the notion that ASMs are sensitive to environmental factors such as rotenone and may alter the risk of neurological disease later in life by disrupting neuronal development.

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate firing of globus pallidus neurons in vivo

Cited by 18 publications

References 54 publications

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

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

Adenosine A2A Receptor Modulates the Activity of Globus Pallidus Neurons in Rats

The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure

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