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 (I(CAN)) in preBötC neurons. We also found that high concentrations of intracellular BAPTA, a high-affinity Ca2+ chelator, and the I(CAN) antagonist flufenamic acid (FFA) decreased the magnitude of drive potentials. We conclude that I(CAN) 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.
Pace
Ryland W
RW
Department of Applied Science, McGlothlin-Street Hall, Room 303, The College of William and Mary, Williamsburg, VA 23187-8795, USA.
Mackay
Devin D
DD
Feldman
Jack L
JL
Del Negro
Christopher A
CA
D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005439:Flufenamic Acid / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D001239:Inhalation / Q000187:drug effects / Q000502:physiology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010507:Periodicity; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA / Q000378:metabolism; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012125:Respiratory Center / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
D002614:Chelating Agents; C578936:Grm5 protein, mouse; D053496:Inositol 1,4,5-Trisphosphate Receptors; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D004533:Egtazic Acid; D005439:Flufenamic Acid; D015544:Inositol 1,4,5-Trisphosphate; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium