Inspiratory bursts in the preBötzinger complex depend on a calcium‐activated non‐specific cation current linked to glutamate receptors in neonatal mice

Inspiratory neurons of the preBötzinger complex (preBötC) form local excitatory networks and display 10–30 mV transient depolarizations, dubbed inspiratory drive potentials, with superimposed spiking. AMPA receptors are critical for rhythmogenesis under normal conditions in vitro but whether other postsynaptic mechanisms contribute to drive potential generation remains unknown. We examined synaptic and intrinsic membrane properties that generate inspiratory drive potentials in preBötC neurons using neonatal mouse medullary slice preparations that generate respiratory rhythm. We found that NMDA receptors, group I metabotropic glutamate receptors (mGluRs), but not group II mGluRs, contributed to inspiratory drive potentials. Subtype 1 of the group I mGluR family (mGluR1) probably regulates a K+ channel, whereas mGluR5 operates via an inositol 1,4,5‐trisphosphate (IP3) receptor‐dependent mechanism to augment drive potential generation. We tested for and verified the presence of a Ca2+‐activated non‐specific cation current (ICAN) in preBötC neurons. We also found that high concentrations of intracellular BAPTA, a high‐affinity Ca2+ chelator, and the ICAN antagonist flufenamic acid (FFA) decreased the magnitude of drive potentials. We conclude that ICAN underlies robust inspiratory drive potentials in preBötC neurons, and is only fully evoked by ionotropic and metabotropic glutamatergic synaptic inputs, i.e. by network activity.

[1]  J. Feldman,et al.  Role of persistent sodium current in mouse preBötzinger Complex neurons and respiratory rhythm generation , 2007, The Journal of physiology.

[2]  Chi-Minh Tuong,et al.  Functional imaging reveals respiratory network activity during hypoxic and opioid challenge in the neonate rat tilted sagittal slab preparation. , 2007, Journal of neurophysiology.

[3]  G. Funk,et al.  High Sensitivity to Neuromodulator-Activated Signaling Pathways at Physiological [K+] of Confocally Imaged Respiratory Center Neurons in On-Line-Calibrated Newborn Rat Brainstem Slices , 2006, The Journal of Neuroscience.

[4]  J. Ramirez,et al.  Gasping Activity In Vitro: A Rhythm Dependent on 5-HT2A Receptors , 2006, The Journal of Neuroscience.

[5]  A. Nistri,et al.  Tuning and playing a motor rhythm: how metabotropic glutamate receptors orchestrate generation of motor patterns in the mammalian central nervous system , 2006, The Journal of physiology.

[6]  Ben W. Strowbridge,et al.  Blanes Cells Mediate Persistent Feedforward Inhibition onto Granule Cells in the Olfactory Bulb , 2006, Neuron.

[7]  M. Hasselmo,et al.  Mechanism of Graded Persistent Cellular Activity of Entorhinal Cortex Layer V Neurons , 2006, Neuron.

[8]  J. Ramirez,et al.  Pattern-specific synaptic mechanisms in a multifunctional network. II. Intrinsic modulation by metabotropic glutamate receptors. , 2006, Journal of neurophysiology.

[9]  J. Feldman,et al.  Looking for inspiration: new perspectives on respiratory rhythm , 2006, Nature Reviews Neuroscience.

[10]  J. Feldman,et al.  Distinct rhythm generators for inspiration and expiration in the juvenile rat , 2006, The Journal of physiology.

[11]  D. Attwell,et al.  Neuroenergetics and the kinetic design of excitatory synapses , 2005, Nature Reviews Neuroscience.

[12]  Jan-Marino Ramirez,et al.  Postnatal development differentially affects voltage-activated calcium currents in respiratory rhythmic versus nonrhythmic neurons of the pre-Bötzinger complex. , 2005, Journal of neurophysiology.

[13]  M. Hollmann,et al.  Kinetics and subunit composition of NMDA receptors in respiratory‐related neurons , 2005, Journal of neurochemistry.

[14]  R. Vennekens,et al.  Comparison of functional properties of the Ca2+-activated cation channels TRPM4 and TRPM5 from mice. , 2005, Cell calcium.

[15]  Craig Montell,et al.  The TRP Superfamily of Cation Channels , 2005, Science's STKE.

[16]  J. Feldman,et al.  Sodium and Calcium Current-Mediated Pacemaker Neurons and Respiratory Rhythm Generation , 2005, The Journal of Neuroscience.

[17]  A. Nistri,et al.  Activation of group I metabotropic glutamate receptors enhances efficacy of glutamatergic inputs to neonatal rat hypoglossal motoneurons in vitro , 2004, The European journal of neuroscience.

[18]  Y. Schiller.  Activation of a calcium-activated cation current during epileptiform discharges and its possible role in sustaining seizure-like events in neocortical slices. , 2004, Journal of neurophysiology.

[19]  Jan-Marino Ramirez,et al.  Differential Contribution of Pacemaker Properties to the Generation of Respiratory Rhythms during Normoxia and Hypoxia , 2004, Neuron.

[20]  J. Feldman,et al.  Synaptic activity-independent persistent plasticity in endogenously active mammalian motoneurons , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  A. Munhall,et al.  Calcium‐dependent subthreshold oscillations determine bursting activity induced by N‐methyl‐d‐aspartate in rat subthalamic neurons in vitro , 2004, The European journal of neuroscience.

[22]  I. Homma,et al.  Contribution of Ca2+‐dependent conductances to membrane potential fluctuations of medullary respiratory neurons of newborn rats in vitro , 2003, The Journal of physiology.

[23]  A. El Manira,et al.  mGluR1, but not mGluR5, mediates depolarization of spinal cord neurons by blocking a leak current. , 2003, Journal of neurophysiology.

[24]  T. Gudermann,et al.  TRPM5 Is a Voltage-Modulated and Ca2+-Activated Monovalent Selective Cation Channel , 2003, Current Biology.

[25]  Ikuo Homma,et al.  A Novel Functional Neuron Group for Respiratory Rhythm Generation in the Ventral Medulla , 2003, The Journal of Neuroscience.

[26]  M. Hasselmo,et al.  Graded persistent activity in entorhinal cortex neurons , 2002, Nature.

[27]  Robert J Butera,et al.  Persistent sodium current, membrane properties and bursting behavior of pre-bötzinger complex inspiratory neurons in vitro. , 2002, Journal of neurophysiology.

[28]  Consuelo Morgado-Valle,et al.  Respiratory Rhythm An Emergent Network Property? , 2002, Neuron.

[29]  A. Perraud,et al.  TRPM4 Is a Ca2+-Activated Nonselective Cation Channel Mediating Cell Membrane Depolarization , 2002, Cell.

[30]  D. Ypey,et al.  Fenamates: a novel class of reversible gap junction blockers. , 2001, The Journal of pharmacology and experimental therapeutics.

[31]  D. Ogden,et al.  The conductance underlying the parallel fibre slow EPSP in rat cerebellar Purkinje neurones studied with photolytic release of L‐glutamate , 2001, The Journal of physiology.

[32]  D. Richter,et al.  Hypoxic modulation of L-type Ca2+ channels in inspiratory brainstem neurones: Intracellular signalling pathways and metabotropic glutamate receptors , 2000, Brain Research.

[33]  M. Hollmann,et al.  Expression of 15 Glutamate Receptor Subunits and Various Splice Variants in Tissue Slices and Single Neurons of Brainstem Nuclei and Potential Functional Implications , 2000, Journal of neurochemistry.

[34]  C. Valenzuela,et al.  Ca2+ store‐dependent potentiation of Ca2+‐activated non‐selective cation channels in rat hippocampal neurones in vitro , 1999, The Journal of physiology.

[35]  D. Richter,et al.  Calcium currents in respiratory neurons of the cat in vivo , 1999, Pflügers Archiv.

[36]  Jeffrey C. Smith,et al.  Neuronal pacemaker for breathing visualized in vitro , 1999, Nature.

[37]  D. Richter,et al.  Calcium oscillations in rhythmically active respiratory neurones in the brainstem of the mouse , 1999, The Journal of physiology.

[38]  K. Ballanyi,et al.  Synaptic inhibition in the isolated respiratory network of neonatal rats , 1998, The European journal of neuroscience.

[39]  D. Richter,et al.  L‐type Ca2+ channels in inspiratory neurones of mice and their modulation by hypoxia , 1998, The Journal of physiology.

[40]  J. Feldman,et al.  AMPA receptor activation and phosphatase inhibition affect neonatal rat respiratory rhythm generation , 1998, The Journal of physiology.

[41]  M B Jackson,et al.  Single‐Channel Recording , 1998, Current protocols in neuroscience.

[42]  J. Feldman,et al.  Bidirectional electrical coupling between inspiratory motoneurons in the newborn mouse nucleus ambiguus. , 1997, Journal of neurophysiology.

[43]  J. Feldman,et al.  Calcium-dependent plateau potentials in rostral ambiguus neurons in the newborn mouse brain stem in vitro. , 1997, Journal of neurophysiology.

[44]  J. C. Smith,et al.  Functional respiratory rhythm generating networks in neonatal mice lacking NMDAR1 gene. , 1997, Journal of neurophysiology.

[45]  T. Molinski,et al.  Xestospongins: Potent Membrane Permeable Blockers of the Inositol 1,4,5-Trisphosphate Receptor , 1997, Neuron.

[46]  X. Leinekugel,et al.  A Long-Lasting Calcium-Activated Nonselective Cationic Current Is Generated by Synaptic Stimulation or Exogenous Activation of Group I Metabotropic Glutamate Receptors in CA1 Pyramidal Neurons , 1997, The Journal of Neuroscience.

[47]  D. Richter,et al.  Calcium‐dependent responses in neurons of the isolated respiratory network of newborn rats. , 1996, The Journal of physiology.

[48]  J. Champagnat,et al.  Electroresponsive properties and membrane potential trajectories of three types of inspiratory neurons in the newborn mouse brain stem in vitro. , 1996, Journal of neurophysiology.

[49]  I. Greenwood,et al.  Comparison of the effects of fenamates on Ca‐activated chloride and potassium currents in rabbit portal vein smooth muscle cells , 1995, British journal of pharmacology.

[50]  J. Feldman,et al.  Modulation of neural network activity in vitro by cyclothiazide, a drug that blocks desensitization of AMPA receptors , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[51]  L. Toro,et al.  Potentiation of large conductance KCa channels by niflumic, flufenamic, and mefenamic acids. , 1994, Biophysical journal.

[52]  J C Smith,et al.  Generation and transmission of respiratory oscillations in medullary slices: role of excitatory amino acids. , 1993, Journal of neurophysiology.

[53]  L. Trussell,et al.  Desensitization of AMPA receptors upon multiquantal neurotransmitter release , 1993, Neuron.

[54]  M. Mayer,et al.  Activation and desensitization of AMPA/kainate receptors by novel derivatives of willardiine , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[55]  J. C. Smith,et al.  Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals. , 1991, Science.

[56]  J. C. Smith,et al.  Role of excitatory amino acids in the generation and transmission of respiratory drive in neonatal rat. , 1991, The Journal of physiology.

[57]  L. Trussell,et al.  Glutamate receptor desensitization and its role in synaptic transmission , 1989, Neuron.

[58]  W. Tiller.  Dendrites , 1964, Science.

[59]  J. Teulon.  Ca2+-Activated Non-Selective Cation Channels , 2000 .

[60]  B. Marinov,et al.  Dose-dependent potentiation and inhibition of single Ca2+-activated K+ channels by flufenamic acid. , 2000, Membrane & cell biology.

[61]  M. Mishina,et al.  Pharmacology of Ionic Channel Function: Activators and Inhibitors , 2000, Handbook of Experimental Pharmacology.

[62]  Marinov Bs,et al.  Dose-dependent potentiation and inhibition of single Ca2+-activated K+ channels by flufenamic acid. , 2000 .

[63]  J. Feldman,et al.  PreBötzinger complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation. , 1998, Annual review of physiology.