TRPV4 activation at the physiological temperature is a critical determinant of neuronal excitability and behavior
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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.
KeywordsTRPV4 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.).
- 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 PubMedCentralCrossRefPubMedGoogle 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 PubMedCentralCrossRefPubMedGoogle 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 PubMedCentralCrossRefPubMedGoogle 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 CrossRefGoogle Scholar
- 38.Takao K, Miyakawa T (2006) Light/dark transition test for mice. J Vis Exp: 104. doi: 10.3791/104
- 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 CrossRefPubMedGoogle 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 CrossRefGoogle Scholar