Pflügers Archiv - European Journal of Physiology

, Volume 467, Issue 12, pp 2495–2507 | Cite as

TRPV4 activation at the physiological temperature is a critical determinant of neuronal excitability and behavior

  • Koji ShibasakiEmail author
  • Shouta Sugio
  • Keizo Takao
  • Akihiro Yamanaka
  • Tsuyoshi Miyakawa
  • Makoto Tominaga
  • Yasuki Ishizaki
Ion channels, receptors and transporters


For homeothermic animals, constant body temperature is an important determinant of brain function. It is well established that changes in brain temperature dynamically influence hippocampal activity. We previously reported that the thermosensor TRPV4 (activated above 34 °C) is activated at the physiological temperature in hippocampal neurons and controls neuronal excitability in vitro. Here, we examined if TRPV4 regulates neuronal excitability through its activation at the physiological temperature in vivo. We found that TRPV4-deficient (TRPV4KO) mice exhibit reduced depression-like and social behaviors compared to wild-type (WT) mice, and the number of c-fos positive cells in the dentate gyrus was significantly reduced upon the depression-like behaviors. We measured resting membrane potentials (RMPs) in the hippocampal granule cells from slice preparations at 35 °C and found that TRPV4-positive neurons significantly depolarized the RMPs through TRPV4 activation at the physiological temperature. The depolarization increased the spike numbers depending on the enhancement of TRPV4 activation. We also found that theta-frequency electroencephalogram (EEG) activities in TRPV4KO mice during wake periods were significantly reduced compared with those in WT mice. Taken together, we report for the first time that TRPV4 activation at the physiological temperature is important to regulate neuronal excitability and behaviors in mammals.


TRPV4 Brain temperature Synapse Neuron Behavior 



We thank Mrs. S. Mizuno, Y. Kogure, and E. Fukuda (Gunma Univ.) for technical assistance and our lab members for helpful discussion. TRPV4KO mice were kindly provided by Dr. A. Mizuno (Jichi Medical University). This research was supported by Grants-in-Aid for Scientific Research (Project No. 15H05934 <Thermal Biology>, 21200012, 20399554, 24111507 + 26111702 <Brain Environment>, 26117502 <glial assembly>, 15H03000 to K.S.; 23650159 to Y.I.; and 18077012 to M.T.), Integrative Brain Research (IBR-shien), and Innovative Areas (Comprehensive Brain Science Network); from the Ministry of Education, Culture, Sports, Science and Technology, Japan; by a grant from Uehara Memorial Foundation (to K.S.); by a grant from Takeda Science Foundation, Tokyo, Japan (to K.S.); by a grant from the Sumitomo Foundation (to K.S.); by a grant from the Brain Science Foundation (to K.S.); by a grant from Narishige Neuroscience Research Foundation (to K.S.); by a grant from Salt Science Research Foundation No.14C2 (to K.S.); and by a grant from the Ichiro Kanehara Foundation (to K.S.).

Supplementary material

424_2015_1726_Fig9_ESM.gif (419 kb)
Supplementary Figure 1

Detection of c-fos mRNA by in situ hybridization. Scale Bar; 500 μm. (GIF 419 kb)

424_2015_1726_MOESM1_ESM.tif (1.6 mb)
(TIFF 1598 kb)
424_2015_1726_Fig10_ESM.gif (298 kb)
Supplementary Figure 2

Adult neurogenesis is normal in DG of TRPV4KO a, b; Adult neurogenesis was examined in WT or TRPV4KO DGs by incorporation and detection of BrdU (A), or detection of DCX (B). Scale Bars; 200 μm. c, d; Quantification of BrdU+ (C) or DCX+ (D) cell numbers in DG sections (3 independent animals, n = 16 slide glasses). (GIF 298 kb)

424_2015_1726_MOESM2_ESM.tif (1.1 mb)
(TIFF 1171 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Molecular and Cellular NeurobiologyGunma University Graduate School of MedicineMaebashiJapan
  2. 2.Section of Behavior PatternsMaebashiJapan
  3. 3.Division of Cell Signaling, National Institute for Physiological SciencesOkazakiJapan
  4. 4.Okazaki Institute for Integrative BioscienceNational Institutes of Natural SciencesOkazakiJapan
  5. 5.Department of Physiological SciencesThe Graduate University for Advanced StudiesOkazakiJapan
  6. 6.Department of Neuroscience II, Research Institute of Environmental MedicineNagoya UniversityNagoyaJapan
  7. 7.Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST)TokyoJapan
  8. 8.Division of Systems Medicine, Institute for Comprehensive Medical ScienceFujita Health UniversityToyoakeJapan

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