Effects of Body Temperature on Neural Activity in the Hippocampus: Regulation of Resting Membrane Potentials by Transient Receptor Potential Vanilloid 4

Physiological body temperature is an important determinant for neural functions, and it is well established that changes in temperature have dynamic influences on hippocampal neural activities. However, the detailed molecular mechanisms have never been clarified. Here, we show that hippocampal neurons express functional transient receptor potential vanilloid 4 (TRPV4), one of the thermosensitive TRP (transient receptor potential) channels, and that TRPV4 is constitutively active at physiological temperature. Activation of TRPV4 at 37°C depolarized the resting membrane potential in hippocampal neurons by allowing cation influx, which was observed in wild-type (WT) neurons, but not in TRPV4-deficient (TRPV4KO) cells, although dendritic morphology, synaptic marker clustering, and synaptic currents were indistinguishable between the two genotypes. Furthermore, current injection studies revealed that TRPV4KO neurons required larger depolarization to evoke firing, equivalent to WT neurons, indicating that TRPV4 is a key regulator for hippocampal neural excitabilities. We conclude that TRPV4 is activated by physiological temperature in hippocampal neurons and thereby controls their excitability.

[1]  P. Andersen,et al.  Conserved spatial learning in cooled rats in spite of slowing of dentate field potentials , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[2]  D. Julius,et al.  The capsaicin receptor: a heat-activated ion channel in the pain pathway , 1997, Nature.

[3]  C. Belmonte,et al.  The contribution of TRPM8 channels to cold sensing in mammalian neurones , 2005, The Journal of physiology.

[4]  A. Hodgkin,et al.  The effect of temperature on the electrical activity of the giant axon of the squid , 1949, The Journal of physiology.

[5]  M. Blumberg,et al.  Temperature-induced reciprocal activation of hippocampal field activity. , 2004, Journal of neurophysiology.

[6]  S. Gasparini,et al.  Silent synapses in the developing hippocampus: lack of functional AMPA receptors or low probability of glutamate release? , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Trimmer,et al.  Mossy fibre contact triggers the targeting of Kv4.2 potassium channels to dendrites and synapses in developing cerebellar granule neurons , 2004, Journal of neurochemistry.

[8]  V. Flockerzi,et al.  Activation of TRPV4 Channels (hVRL-2/mTRP12) by Phorbol Derivatives* , 2002, The Journal of Biological Chemistry.

[9]  R. A. Davidoff From Neuron to Brain , 1977, Neurology.

[10]  P. Andersen,et al.  Association between brain temperature and dentate field potentials in exploring and swimming rats. , 1993, Science.

[11]  Joseph Thomas Velardo,et al.  A Textbook of General Physiology , 1960, The Yale Journal of Biology and Medicine.

[12]  J. Levine,et al.  Hypotonicity Induces TRPV4-Mediated Nociception in Rat , 2003, Neuron.

[13]  B. Gustafsson,et al.  Spontaneous Unitary Synaptic Activity in CA1 Pyramidal Neurons during Early Postnatal Development: Constant Contribution of AMPA and NMDA Receptors , 2002, The Journal of Neuroscience.

[14]  T. Fay,et al.  OBSERVATIONS ON REFLEX RESPONSES DURING PROLONGED PERIODS OF HUMAN REFRIGERATION , 1941 .

[15]  J. M. Ritchie,et al.  The effect of cooling on the size of the action potential of mammalian non‐medullated fibres , 1956, The Journal of physiology.

[16]  J. Trimmer Regulation of ion channel expression by cytoplasmic subunits , 1998, Current Opinion in Neurobiology.

[17]  A. Basbaum,et al.  The Cloned Capsaicin Receptor Integrates Multiple Pain-Producing Stimuli , 1998, Neuron.

[18]  Bernd Nilius,et al.  TRPV4 calcium entry channel: a paradigm for gating diversity. , 2004, American journal of physiology. Cell physiology.

[19]  B. Nilius,et al.  Heat-evoked Activation of TRPV4 Channels in a HEK293 Cell Expression System and in Native Mouse Aorta Endothelial Cells* , 2002, The Journal of Biological Chemistry.

[20]  D. Prince,et al.  Temperature dependence of intrinsic membrane properties and synaptic potentials in hippocampal CA1 neurons in vitro , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  M. Schaefer,et al.  Human TRPV4 Channel Splice Variants Revealed a Key Role of Ankyrin Domains in Multimerization and Trafficking* , 2006, Journal of Biological Chemistry.

[22]  Makoto Tominaga,et al.  Heat-Evoked Activation of the Ion Channel, TRPV4 , 2002, The Journal of Neuroscience.

[23]  P Facer,et al.  Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2. , 2001, Physiological genomics.

[24]  B. Sakmann,et al.  Adjacent asparagines in the NR2‐subunit of the NMDA receptor channel control the voltage‐dependent block by extracellular Mg2+ , 1998, The Journal of physiology.

[25]  Y. Okada,et al.  The effects of cooling and rewarming on the neuronal activity of pyramidal neurons in guinea pig hippocampal slices , 2001, Brain Research.

[26]  H. Takebayashi,et al.  Expression of the basic helix-loop-factor Olig2 in the developing retina: Olig2 as a new marker for retinal progenitors and late-born cells. , 2007, Gene expression patterns : GEP.

[27]  A. Hudspeth,et al.  Vanilloid Receptor–Related Osmotically Activated Channel (VR-OAC), a Candidate Vertebrate Osmoreceptor , 2000, Cell.

[28]  G. Bernardi,et al.  Presynaptic Facilitation of Glutamatergic Synapses to Dopaminergic Neurons of the Rat Substantia Nigra by Endogenous Stimulation of Vanilloid Receptors , 2003, The Journal of Neuroscience.

[29]  B. Nilius,et al.  Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels , 2003, Nature.

[30]  R. Nicoll,et al.  Expression mechanisms underlying long-term potentiation: a postsynaptic view. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[31]  J. Friedman,et al.  Abnormal osmotic regulation in trpv4-/- mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  P Andersen,et al.  Brain temperature and hippocampal function , 1995, Hippocampus.

[33]  G. Somjen,et al.  The effects of temperature on synaptic transmission in hippocampal tissue slices , 1985, Brain Research.

[34]  M. Imai,et al.  Impaired osmotic sensation in mice lacking TRPV4. , 2003, American journal of physiology. Cell physiology.

[35]  R. Nicoll,et al.  Long-term potentiation--a decade of progress? , 1999, Science.

[36]  K. Kodaira,et al.  Impaired Pressure Sensation in Mice Lacking TRPV4* , 2003, Journal of Biological Chemistry.

[37]  U. Wissenbach,et al.  Differential activation of the volume-sensitive cation channel TRP12 (OTRPC4) and volume-regulated anion currents in HEK-293 cells , 2001, Pflügers Archiv.

[38]  S. Heller,et al.  Vertebrate and invertebrate TRPV-like mechanoreceptors. , 2003, Cell calcium.

[39]  G. Schultz,et al.  OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity , 2000, Nature Cell Biology.

[40]  M. Freichel,et al.  Trp12, a novel Trp related protein from kidney , 2000, FEBS letters.

[41]  John A. Wemmie,et al.  The Acid-Activated Ion Channel ASIC Contributes to Synaptic Plasticity, Learning, and Memory , 2002, Neuron.

[42]  H. von Gersdorff,et al.  Fine-Tuning an Auditory Synapse for Speed and Fidelity: Developmental Changes in Presynaptic Waveform, EPSC Kinetics, and Synaptic Plasticity , 2000, The Journal of Neuroscience.

[43]  James S Trimmer,et al.  A Novel Targeting Signal for Proximal Clustering of the Kv2.1 K+ Channel in Hippocampal Neurons , 2000, Neuron.

[44]  J. Trimmer,et al.  Differential spatiotemporal expression of K+ channel polypeptides in rat hippocampal neurons developing in situ and in vitro , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[45]  E. Hartveit,et al.  Functional Properties of Spontaneous EPSCs and non‐NMDA Receptors in Rod Amacrine (AII) Cells in the Rat Retina , 2003, The Journal of physiology.