title: Glial cell-expressed mechanosensitive channel TRPV4 mediates infrasound-induced neuronal impairment.
abstract: Vibroacoustic disease, a progressive and systemic disease, mainly involving the central nervous system, is caused by excessive exposure to low-frequency but high-intensity noise generated by various heavy transportations and machineries. Infrasound is a type of low-frequency noise. Our previous studies demonstrated that infrasound at a certain intensity caused neuronal injury in rats but the underlying mechanism(s) is still largely unknown. Here, we showed that glial cell-expressed TRPV4, a Ca(2+)-permeable mechanosensitive channel, mediated infrasound-induced neuronal injury. Among different frequencies and intensities, infrasound at 16 Hz and 130 dB impaired rat learning and memory abilities most severely after 7-14 days exposure, a time during which a prominent loss of hippocampal CA1 neurons was evident. Infrasound also induced significant astrocytic and microglial activation in hippocampal regions following 1- to 7-day exposure, prior to neuronal apoptosis. Moreover, pharmacological inhibition of glial activation in vivo protected against neuronal apoptosis. In vitro, activated glial cell-released proinflammatory cytokines IL-1β and TNF-α were found to be key factors for this neuronal apoptosis. Importantly, infrasound induced an increase in the expression level of TRPV4 both in vivo and in vitro. Knockdown of TRPV4 expression by siRNA or pharmacological inhibition of TRPV4 in cultured glial cells decreased the levels of IL-1β and TNF-α, attenuated neuronal apoptosis, and reduced TRPV4-mediated Ca(2+) influx and NF-κB nuclear translocation. Finally, using various antagonists we revealed that calmodulin and protein kinase C signaling pathways were involved in TRPV4-triggered NF-κB activation. Thus, our results provide the first evidence that glial cell-expressed TRPV4 is a potential key factor responsible for infrasound-induced neuronal impairment.
authors.affiliation: Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China, biomidas@fmmu.edu.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.forename: Fang
authors.initials: F
authors.lastname: Du
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Cai
authors.forename: Guo-Feng
authors.initials: GF
authors.lastname: Zhang
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Xu
authors.forename: Tian
authors.initials: T
authors.lastname: Lin
authors.forename: Hao-Ran
authors.initials: HR
authors.lastname: Cheng
authors.forename: Xue-Dong
authors.initials: XD
authors.lastname: Liu
authors.forename: Li-Ze
authors.initials: LZ
authors.lastname: Xiong
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D001522:Behavior, Animal / Q000528:radiation effects*; D015153:Blotting, Western; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000528:radiation effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D018782:Maze Learning / Q000528:radiation effects; D008465:Mechanoreceptors / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000528:radiation effects*; D009474:Neurons / Q000378:metabolism / Q000528:radiation effects*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013016:Sound / Q000009:adverse effects*; D050916:TRPV Cation Channels / Q000378:metabolism*; D014162:Transfection
chemical_list: D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat