Inhibition of Inwardly Rectifying Potassium (Kir) 4.1 Channels Facilitates Brain-Derived Neurotrophic Factor (BDNF) Expression in Astrocytes

Kinboshi, Masato; Mukai, Takahiro; Nagao, Yuki; Matsuba, Yusuke; Tsuji, Yoshimi; Tanaka, Shiho; Tokudome, Kentaro; Shimizu, Saki; Ito, Hidefumi; Ikeda, Akio; Inanobe, Atsushi; Kurachi, Yoshihisa; Inoue, Shintaro; Ohno, Yukihiro

doi:10.3389/fnmol.2017.00408

Cited by 38 publications

(47 citation statements)

References 67 publications

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“… 57 Astrocytic Kir4.1 channels are blocked by antidepressants and it was recently shown that small interfering RNA–mediated knockdown of Kir4.1 channels in cultured astrocytes is sufficient to increase BDNF expression. 58 However, direct effects of monoamines through their receptors on BDNF expression in astrocytes may not be ruled out just yet. It is shown that dopamine as well as norepinephrine induces BDNF expression in cultured astrocytes.…”

Section: Brain-derived Neurotrophic Factormentioning

confidence: 99%

Effects of Monoamines and Antidepressants on Astrocyte Physiology: Implications for Monoamine Hypothesis of Depression

et al. 2018

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Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders affecting over one-fifth of the population worldwide. Owing to our limited understanding of the pathophysiology of MDD, the quest for finding novel antidepressant drug targets is severely impeded. Monoamine hypothesis of MDD provides a robust theoretical framework, forming the core of a large jigsaw puzzle, around which we must look for the vital missing pieces. Growing evidence suggests that the glial loss observed in key regions of the limbic system in depressed patients, at least partly, accounts for the structural and cognitive manifestations of MDD. Studies in animal models have subsequently hinted at the possibility that the glial atrophy may play a causative role in the precipitation of depressive symptoms. Antidepressants as well as monoamine neurotransmitters exert profound effects on the gene expression and metabolism in astrocytes. This raises an intriguing possibility that the astrocytes may play a central role alongside neurons in the behavioral effects of antidepressant drugs. In this article, we discuss the gene expression and metabolic changes brought about by antidepressants in astrocytes, which could be of relevance to synaptic plasticity and behavioral effects of antidepressant treatments.

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Section: Brain-derived Neurotrophic Factormentioning

confidence: 99%

Effects of Monoamines and Antidepressants on Astrocyte Physiology: Implications for Monoamine Hypothesis of Depression

et al. 2018

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“…Therefore, dysfunction of Kir4.1 channels elevates not only extracellular K + , but also glutamate levels at tripartite synapses (Ohno et al, 2015 ; Ohno, 2018 ). Furthermore, we recently demonstrated that inhibition (channel blockade or expressional suppression) of Kir4.1 channels facilitated the expression of brain-derived neurotrophic factor (BDNF) in astrocytes, which may produce diverse effects including synaptic plasticity, neural sprouting, neurogenesis and reactive gliosis in the brain (Kinboshi et al, 2017a ; Ohno, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Antiepileptic Drugs Elevate Astrocytic Kir4.1 Expression in the Rat Limbic Region

et al. 2018

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Inwardly rectifying potassium (Kir) channel subunits Kir4.1 are specifically expressed in astrocytes and regulate neuronal excitability by mediating spatial potassium buffering. In addition, it is now known that astrocytic Kir4.1 channels are closely involved in the pathogenesis of epilepsy. Here, to explore the role of Kir4.1 channels in the treatment of epilepsy, we evaluated the effects of the antiepileptic drugs, valproate, phenytoin, phenobarbital and ethosuximide, on Kir4.1 expression in astrocytes using immunohistochemical techniques. Repeated treatment of rats with valproate (30–300 mg/kg, i.p., for 1–10 days) significantly elevated the Kir4.1 expression levels in the cerebral cortex, amygdala and hippocampus. Up-regulation of Kir4.1 expression by valproate occurred in a dose- and treatment period-related manner, and did not accompany an increase in the number of astrocytes probed by glial fibrillary acidic protein (GFAP). In addition, repeated treatment with phenytoin (30 mg/kg, i.p., for 10 days) or phenobarbital (30 mg/kg, i.p., for 10 days) also elevated Kir4.1 expression region-specifically in the amygdala. However, ethosuximide (100 mg/kg, i.p., for 10 days), which can alleviate absence but not convulsive seizures, showed no effects on the astrocytic Kir4.1 expression. The present results demonstrated for the first time that the antiepileptic drugs effective for convulsive seizures (valproate, phenytoin, and phenobarbital) commonly elevate the astrocytic Kir4.1 channel expression in the limbic regions, which may be related to their antiepileptic actions.

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“…Kir4.1 expression is significantly reduced in models of epilepsy (Ivens et al, ; Kinboshi et al, ; Nagao et al, ; Ohno, ; Zurolo et al, ) and after traumatic CNS injury (Olsen et al, ; Pivonkova, Benesova, Butenko, Chvatal, & Anderova, ; Stewart et al, ) but little is known regarding the underlying molecular mechanism contributing to Kir4.1 protein and mRNA reductions. We used a LiPilo model of SE to examine changes in Kir4.1 expression in the hippocampus during the development of epilepsy after a primary insult.…”

Section: Resultsmentioning

confidence: 99%

DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

Boni

Kahanovitch

Nwaobi

et al. 2020

Glia

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Kir4.1, a glial-specific inwardly rectifying potassium channel, is implicated in astrocytic maintenance of K + homeostasis. Underscoring the role of Kir4.1 in central nervous system (CNS) functioning, genetic mutations in KCNJ10, the gene which encodes Kir4.1, causes seizures, ataxia and developmental disability in humans.Kir4.1 protein and mRNA loss are consistently observed in CNS injury and neurological diseases linked to hyperexcitability and neuronal dysfunction, leading to the notion that Kir4.1 represents an attractive therapeutic target. Despite this, little is understood regarding the mechanisms that underpin this downregulation. Previous work by our lab revealed that DNA hypomethylation of the Kcnj10 gene functions to regulate mRNA levels during astrocyte maturation whereas hypermethylation in vitro led to decreased promoter activity. In the present study, we utilized two vastly different injury models with known acute and chronic loss of Kir4.1 protein and mRNA to evaluate the methylation status of Kcnj10 as a candidate molecular mechanism for reduced transcription and subsequent protein loss. Examining whole hippocampal tissue and isolated astrocytes, in a lithium-pilocarpine model of epilepsy, we consistently identified hypermethylation of CpG island two, which resides in the large intronic region spanning the Kcnj10 gene. Strikingly similar results were observed using the second injury paradigm, a fifth cervical (C5) vertebral hemi-contusion model of spinal cord injury. Our previous work indicates the same gene region is significantly hypomethylated when transcription increases during astrocyte maturation.Our results suggest that DNA methylation can bidirectionally modulate Kcnj10 transcription and may represent a targetable molecular mechanism for the restoring astroglial Kir4.1 expression following CNS insult. K E Y W O R D S astrocyte, DNA methylation, Kcnj10, Kir4.1, Pilocarpine

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Inhibition of Inwardly Rectifying Potassium (Kir) 4.1 Channels Facilitates Brain-Derived Neurotrophic Factor (BDNF) Expression in Astrocytes

Cited by 38 publications

References 67 publications

Effects of Monoamines and Antidepressants on Astrocyte Physiology: Implications for Monoamine Hypothesis of Depression

Effects of Monoamines and Antidepressants on Astrocyte Physiology: Implications for Monoamine Hypothesis of Depression

Antiepileptic Drugs Elevate Astrocytic Kir4.1 Expression in the Rat Limbic Region

DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

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