Transient receptor potential melastatin 2 governs stress-induced depressive-like behaviors

Ko, Seung Yeon; Wang, Sung Eun; Lee, Han Kyu; Jo, Sungsin; Han, Jinil; Lee, Jun Young; Choi, Mark; Jo, Hye Ryeong; Seo, Jee Young; Jung, Sung Jun; Son, Hyeon

doi:10.1073/pnas.1814335116

Cited by 27 publications

(23 citation statements)

References 46 publications

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“…As mentioned in the introduction, microglial cell-mediated neuroinflammation is a well-recognized factor in the pathogenesis of many other CNS conditions besides the aforementioned conditions. Research has also implicated TRPM2 channel in PD ( Sun et al, 2018 ; An et al, 2019 ; Li and Jiang, 2019 ), MS ( Tsutsui et al, 2018 ), traumatic brain damage ( Cook et al, 2010 ; Yürüker et al, 2015 ), and neurodevelopmental disorders such as ASD ( Higashida et al, 2018 ) and depression ( Xu et al, 2006 ; Jang et al, 2015 ; Zhong et al, 2016 ; Ko et al, 2019 ) as well as ischemic stroke brain damage. Evidently, further research is required to investigate whether the TRPM2 channel in microglial cells in mediating neuroinflammation plays a significant role in these CNS conditions.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

TRPM2 Channel in Microglia as a New Player in Neuroinflammation Associated With a Spectrum of Central Nervous System Pathologies

et al. 2019

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Microglial cells in the central nervous system (CNS) are crucial in maintaining a healthy environment for neurons to function properly. However, aberrant microglial cell activation can lead to excessive generation of neurotoxic proinflammatory mediators and neuroinflammation, which represents a contributing factor in a wide spectrum of CNS pathologies, including ischemic stroke, traumatic brain damage, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, psychiatric disorders, autism spectrum disorders, and chronic neuropathic pain. Oxidative stress is a salient and common feature of these conditions and has been strongly implicated in microglial cell activation and neuroinflammation. The transient receptor potential melastatin-related 2 (TRPM2) channel, an oxidative stress-sensitive calcium-permeable cationic channel, is highly expressed in microglial cells. In this review, we examine the recent studies that provide evidence to support an important role for the TRPM2 channel, particularly TRPM2-mediated Ca2+ signaling, in mediating microglial cell activation, generation of proinflammatory mediators and neuroinflammation, which are of relevance to CNS pathologies. These findings lead to a growing interest in the TRPM2 channel, a new player in neuroinflammation, as a novel therapeutic target for CNS diseases.

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Section: Summary and Perspectivesmentioning

confidence: 99%

TRPM2 Channel in Microglia as a New Player in Neuroinflammation Associated With a Spectrum of Central Nervous System Pathologies

et al. 2019

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“…Hippocampal cultured neurons and brains were processed as described previously ( Ko et al, 2019 ). Mice were decapitated and hippocampi were collected for Western blotting 12 h after the final behavioral task or the last stressor of the CUS paradigm.…”

Section: Methodsmentioning

confidence: 99%

LGI1 governs neuritin-mediated resilience to chronic stress

Lee

Kim

Choi

et al. 2021

Neurobiology of Stress

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Depression is accompanied by neuronal atrophy and decreased neuroplasticity. Leucine-rich glioma-inactivated protein 1 (LGI1), a metastasis suppressor, plays an important role in the development of CNS synapses. We found that LGI1 expression was reduced in the hippocampi of mice that underwent chronic unpredictable stress (CUS), and could be rescued by the antidepressant, fluoxetine. Recombinant soluble neuritin, an endogenous protein previously implicated in antidepressant-like behaviors, elevated hippocampal LGI1 expression in a manner dependent on histone deacetylase 5 (HDAC5) phosphorylation. Accordingly, Nrn1 flox/flox ;Pomc-cre ( Nrn1 cOE) mice, which conditionally overexpress neuritin, displayed increases in hippocampal LGI1 level under CUS and exhibited resilience to CUS that were blocked by hippocampal depletion of LGI1. Interestingly, neuritin-mediated LGI1 expression was inhibited by HNMPA-(AM) 3 , an insulin receptor inhibitor, as was neuritin-mediated HDAC5 phosphorylation. We thus establish hippocampal LGI1 as an effector of neurite outgrowth and stress resilience, and suggest that HDAC5-LGI1 plays a critical role in ameliorating pathological depression.

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“…The following analyzing method was previously described [18]. The gene expression microarray dataset was obtained from the Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) with accession number GSE53987.…”

Section: Methodsmentioning

confidence: 99%

Downregulation of SIRT2 by Chronic Stress Reduces Expression of Synaptic Plasticity-related Genes through the Upregulation of Ehmt2

Wang

et al. 2019

Exp Neurobiol

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Silent information regulator 2 (Sirtuin2 / SIRT2) is a NAD+-dependent deacetylase that regulates the cellular oxidative stress response. It modulates transcriptional silencing and protein stability through deacetylation of target proteins including histones. Previous studies have shown that SIRT2 plays a role in mood disorders and hippocampus-dependent cognitive function, but the underlying neurobiological mechanism is poorly understood. Here, we report that chronic stress suppresses SIRT2 expression in the hippocampus. Molecular and biochemical analyses indicate that the stress-induced decrease in the SIRT2 expression downregulates synaptic plasticity-related genes in the hippocampus through the increase of euchromatic histone-lysine N-methyltransferase 2 (Ehmt2) (also known as G9a). shRNA-mediated knockdown of SIRT2 in the dentate gyrus alters the expression of synaptic plasticity-related genes in a way similar to those induced by chronic stress, and produces depression-like behaviors. Our results indicate that SIRT2 plays an important role in the response to stress, thereby modulating depression-like behaviors.

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Transient receptor potential melastatin 2 governs stress-induced depressive-like behaviors

Cited by 27 publications

References 46 publications

TRPM2 Channel in Microglia as a New Player in Neuroinflammation Associated With a Spectrum of Central Nervous System Pathologies

TRPM2 Channel in Microglia as a New Player in Neuroinflammation Associated With a Spectrum of Central Nervous System Pathologies

LGI1 governs neuritin-mediated resilience to chronic stress

Downregulation of SIRT2 by Chronic Stress Reduces Expression of Synaptic Plasticity-related Genes through the Upregulation of Ehmt2

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