Skip to main content

Advertisement

SpringerLink
Log in

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

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Alessandri-Haber N, Yeh JJ, Boyd AE, Parada CA, Chen X, Reichiling DB, Levine JD (2003) Hypotonicity induces TRPV4-mediated nociception in rat. Neuron 39:497–511

    Article  CAS  PubMed  Google Scholar 

  2. Anderson P, Moser EI (1995) Brain temperature and hippocampal function. Hippocampus 5:491–498

    Article  Google Scholar 

  3. Auer-Grumbach M, Olschewski A, Papic L, Kremer H, McEntagart ME, Uhrig S, Fischer C, Frohlich E, Balint Z, Tang B, Strohmaier H, Lochmuller H, Schlotter-Weigel B, Senderek J, Krebs A, Dick KJ, Petty R, Longman C, Anderson NE, Padberg GW, Schelhaas HJ, van Ravenswaaij-Arts CMA, Pieber TR, Crosby AH, Guelly C (2010) Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat Genet 42:160–U196. doi:10.1038/Ng.508

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. de la Pena E, Malkia A, Cabedo H, Belmonte C, Viana F (2005) The contribution of TRPM8 channels to cold sensing in mammalian neurones. J Physiol 567:415–426

    Article  PubMed Central  PubMed  Google Scholar 

  5. Delany NS, Hurle M, Facer P, Alnadaf T, Plumpton C, Kinghorn I, See CG, Costigan M, Anand P, Woolf CJ, Crowther D, Sanseau P, Tate SN (2001) Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2. Physiol Genomics 4:165–174

    CAS  PubMed  Google Scholar 

  6. Fay T, Smith GW (1941) Observations on reflex responses during prolonged periods of human refrigeration. Arch Neurol Psychiat 45:215–222

    Article  Google Scholar 

  7. Fuster JM, Bauer RH (1974) Visual short-term memory deficit from hypothermia of frontal cortex. Brain Res 81:393–400

    Article  CAS  PubMed  Google Scholar 

  8. Gasparini S, Saviane C, Voronin LL, Cherubini E (2000) Silent synapses in the developing hippocampus: lack of functional AMPA receptors or low probability of glutamate release? Proc Natl Acad Sci U S A 97:9741–9746

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Groc L, Gustafsson B, Hanse E (2002) Spontaneous unitary synaptic activity in CA1 pyramidal neurons during early postnatal development: constant contribution of AMPA and NMDA receptors. J Neurosci 22:5552–5562

    CAS  PubMed  Google Scholar 

  10. Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450

    CAS  PubMed  Google Scholar 

  11. Guler AD, Lee H, Iida T, Shimizu I, Tominaga M, Caterina M (2002) Heat-evoked activation of the ion channel, TRPV4. J Neurosci 22:6408–6414

    CAS  PubMed  Google Scholar 

  12. Hodgkin AI, Katz B (1949) The effect of temperature on the electrical activity of the giant axon of the squid. J Physiol 109:240–249

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Kang SS, Shin SH, Auh CK, Chun J (2012) Human skeletal dysplasia caused by a constitutive activated transient receptor potential vanilloid 4 (TRPV4) cation channel mutation. Exp Mol Med 44:707–722. doi:10.3858/emm.2012.44.12.080

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Karlsson KA, Blumberg MS (2004) Temperature-induced reciprocal activation of hippocampal field activity. J Neurophysiol 91:583–588

    Article  PubMed  Google Scholar 

  15. Komada M, Takao K, Miyakawa T (2008) Elevated plus maze for mice. J Vis Exp. doi:10.3791/1088

    PubMed Central  PubMed  Google Scholar 

  16. Kortner G, Schildhauer K, Petrova O, Schmidt I (1993) Rapid changes in metabolic cold defense and GDP binding to brown adipose tissue mitochondria of rat pups. Am J Physiol 264:R1017–1023

    CAS  PubMed  Google Scholar 

  17. Landoure G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H, Shi YJ, Taye AA, Kong LL, Munns CH, Choo SS, Phelps CB, Paudel R, Houlden H, Ludlow CL, Caterina MJ, Gaudet R, Kleta R, Fischbeck KH, Sumner CJ (2010) Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet 42:170–U109. doi:10.1038/Ng.512

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S (2000) Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertibrate osmoreceptor. Cell 103:525–535

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Liedtke W, Friedman JM (2003) Abnormal osmotic regulation in trpv4−/− mice. Proc Natl Acad Sci U S A 100:13698–13703

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, Caron MG, Tonegawa S (2003) Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc Natl Acad Sci U S A 100:8987–8992. doi:10.1073/pnas.1432926100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Mizuno A, Matsumoto N, Imai M, Suzuki M (2003) Impaired osmotic sensation in mice lacking TRPV4. Am J Physiolol Cell Physiol 285:C96–C101

    Article  CAS  Google Scholar 

  22. Mizuno H, Suzuki Y, Watanabe M, Sokabe T, Yamamoto T, Hattori R, Gotoh M, Tominaga M (2014) Potential role of transient receptor potential (TRP) channels in bladder cancer cells. J Physiol Sci 64:305–314. doi:10.1007/s12576-014-0319-6

    Article  CAS  PubMed  Google Scholar 

  23. Moser E, Mathiesen I, Andersen P (1993) Association between brain temperature and dentate field potentials in exploring and swimming rats. Science 259:1324–1326

    Article  CAS  PubMed  Google Scholar 

  24. Moser EI, Andersen P (1994) Conserved spatial learning in cooled rats in spite of slowing of dentate field potentials. J Neurosci 14:4458–4466

    CAS  PubMed  Google Scholar 

  25. Mutai H, Heller S (2003) Vertebrate and invertibrate TRPV-like mechanoreceptor. Cell Calcium 33:471–478

    Article  CAS  PubMed  Google Scholar 

  26. Nilius B, Prenen J, Wissenbach U, Bodding M, Droogmans G (2001) Differential activation of the volume-sensitive cation channel TRP12 (OTRPC4) and volume-regulated anion currents in HEK-293 cells. Pflugers Arch 443:227–233

    Article  CAS  PubMed  Google Scholar 

  27. Nillius B, Vriens J, Prenen J, Droogmans G, Voets T (2004) TRPV4 calcium entry channel: a paradigm for gating diversity. Am J Physiolol Cell Physiol 286:C195–C205

    Article  Google Scholar 

  28. Ritchie JM, Straub RW (1956) The effect of cooling on the size of the action potential of mammalian non-medullated fibers. J Physiol 134:712–717

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Schiff SJ, Somjen GG (1985) The effects of temperature on synaptic transmission in hippocampal tissue slices. Brain Res 345:279–284

    Article  CAS  PubMed  Google Scholar 

  30. Shibasaki K, Ishizaki Y, Mandadi S (2013) Astrocytes express functional TRPV2 ion channels. Biochem Biophys Res Commun 441:327–332. doi:10.1016/j.bbrc.2013.10.046

    Article  CAS  PubMed  Google Scholar 

  31. Shibasaki K, Nakahira K, Trimmer JS, Shibata R, Akita M, Watanabe S, Ikenaka K (2004) Mossy fibre contact triggers the targeting of Kv4.2 potassium channels to dendrites and synapses in developing cerebellar granule neurons. J Neurochem 89:897–907

    Article  CAS  PubMed  Google Scholar 

  32. Shibasaki K, Suzuki M, Mizuno A, Tominaga M (2007) Effects of body temperature on neural activity in the hippocampus: regulation of resting membrane potentials by transient receptor potential vanilloid 4. J Neuroscience :Off J Soc Neuroscience 27:1566–1575. doi:10.1523/JNEUROSCI.4284-06.2007

    Article  CAS  Google Scholar 

  33. Shibasaki K, Takebayashi H, Ikenaka K, Feng L, Gan L (2007) Expression of the basic helix-loop-factor Olig2 in the developing retina: Olig2 as a new marker for retinal progenitors and late-born cells. Gene Expr Patterns 7:57–65

    Article  CAS  PubMed  Google Scholar 

  34. Shibasaki K, Tominaga M, Ishizaki Y (2015) Hippocampal neuronal maturation triggers post-synaptic clustering of brain temperature-sensor TRPV4. Biochem Biophys Res Commun 458:168–173. doi:10.1016/j.bbrc.2015.01.087

    Article  CAS  PubMed  Google Scholar 

  35. Shuttleworth TJ, Thompson JL (1991) Effect of temperature on receptor-activated changes in [Ca2+]i and their determination using fluorescent probes. J Biol Chem 266:1410–1414

    CAS  PubMed  Google Scholar 

  36. Stortmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD (2000) OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nature Cell Biol 2:695–702

    Article  Google Scholar 

  37. Suzuki M, Mizuno A, Kodaira K, Imai M (2003) Impaired pressure sensation in mice lacking TRPV4. JBiol Chem 278:22664–22668

    Article  CAS  Google Scholar 

  38. Takao K, Miyakawa T (2006) Light/dark transition test for mice. J Vis Exp: 104. doi:10.3791/104

  39. Taschenberger H, von Gersdorff H (2000) Fine-tuning an auditory synapse for speed and fidelity: developmental changes in presynaptic waveform, EPSC kinetics, and synaptic plasticity. J Neurosci 20:9162–9173

    CAS  PubMed  Google Scholar 

  40. Thompson SM, Masukawa LM, Prince DA (1985) Temperature dependence of intrinsic membrane properties and synaptic potentials in hippocampal CA1 neurons in vitro. J Neurosci 5:817–824

    CAS  PubMed  Google Scholar 

  41. Torgersen J, Strand K, Bjelland TW, Klepstad P, Kvale R, Soreide E, Wentzel-Larsen T, Flaatten H (2010) Cognitive dysfunction and health-related quality of life after a cardiac arrest and therapeutic hypothermia. Acta Anaesthesiol Scand 54:721–728. doi:10.1111/j.1399-6576.2010.02219.x

    Article  CAS  PubMed  Google Scholar 

  42. Veruki ML, Morkve SH, Hartveit E (2003) Functional properties of spontaneous EPSCs and non-NMDA receptors in rod amacrine (AII) cells in the rat retina. J Physiol 549:759–774

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Watanabe H, Davis JB, Smart D, Jerman JC, Smith GD, Hayes P, Vriens J, Cairns W, Wissenbach U, Prenen J, Flockerzi V, Droogmans G, Benham CD, Nillius B (2002) Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. J Biol Chem 277:13569–13577

    Article  CAS  PubMed  Google Scholar 

  44. Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nillius B (2003) Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424:434–438

    Article  CAS  PubMed  Google Scholar 

  45. Watanabe H, Vriens J, Suh SH, Benham CD, Droogmans G, Nillius B (2002) Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells. J Biol Chem 277:47044–47051

    Article  CAS  PubMed  Google Scholar 

  46. Wissenbach U, Bodding M, Freichel M, Flockerzi V (2000) Trp12, a novel Trp related protein from kidney. FEBS Letter 485:127–134

    Article  CAS  Google Scholar 

  47. Yuen RKC, Thiruvahindrapuram B, Merico D, Walker S, Tammimies K, Hoang N, Chrysler C, Nalpathamkalam T, Pellecchia G, Liu Y, Gazzellone MJ, D'Abate L, Deneault E, Howe JL, Liu RSC, Thompson A, Zarrei M, Uddin M, Marshall CR, Ring RH, Zwaigenbaum L, Ray PN, Weksberg R, Carter MT, Fernandez BA, Roberts W, Szatmari P, Scherer SW (2015) Whole-genome sequencing of quartet families with autism spectrum disorder. Nat Med 21:97–103. doi:10.1038/Nm.3792

    Article  Google Scholar 

Download references

Acknowledgments

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.).

Author information

Authors and Affiliations

  1. Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan

    Koji Shibasaki, Shouta Sugio & Yasuki Ishizaki

  2. Section of Behavior Patterns, Maebashi, Japan

    Keizo Takao & Tsuyoshi Miyakawa

  3. Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan

    Makoto Tominaga

  4. Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, 444-8585, Japan

    Makoto Tominaga

  5. Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki, 444-8585, Japan

    Makoto Tominaga

  6. Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan

    Akihiro Yamanaka

  7. Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan

    Keizo Takao & Tsuyoshi Miyakawa

  8. Division of Systems Medicine, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, 470-7792, Japan

    Tsuyoshi Miyakawa

Authors
  1. Koji Shibasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shouta Sugio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keizo Takao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akihiro Yamanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tsuyoshi Miyakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Makoto Tominaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasuki Ishizaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Koji Shibasaki.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Figure 1

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

(TIFF 1598 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)

(TIFF 1171 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shibasaki, K., Sugio, S., Takao, K. et al. TRPV4 activation at the physiological temperature is a critical determinant of neuronal excitability and behavior. Pflugers Arch - Eur J Physiol 467, 2495–2507 (2015). https://doi.org/10.1007/s00424-015-1726-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-015-1726-0

Keywords

Search

Navigation