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The Journal of Neuroscience, April 15, 2000, 20(8):2994-3005
The Role of the Hyperpolarization-Activated Current in Modulating
Rhythmic Activity in the Isolated Respiratory Network of
Mice
Muriel
Thoby-Brisson,
Petra
Telgkamp, and
Jan-Marino
Ramirez
Department of Organismal Biology and Anatomy, Committee on
Neurobiology, The University of Chicago, Chicago, Illinois 60637
We examined the role of the hyperpolarization-activated current
(Ih) in the generation of the
respiratory rhythm using a spontaneously active brainstem slice of
mice. This preparation contains the hypoglossus (XII) nucleus, which is
activated in-phase with inspiration and the pre-Bötzinger complex
(PBC), the presumed site for respiratory rhythm generation.
Voltage-clamp recordings (n = 90) indicate that
cesium (Cs) (5 mM) blocked 77.2% of the
Ih current, and ZD 7288 (100 µM) blocked 85.8% of the Ih
current. This blockade increased the respiratory frequency by 161% in
Cs and by 150% in ZD 7288 and increased the amplitude of integrated
population activity in the XII by 97% in Cs and by 162% in ZD 7288, but not in the PBC (Cs, by 19%; ZD 7288, by 4.56%). All inspiratory
PBC neurons (n = 44) recorded in current clamp
within the active network revealed a significantly decreased frequency
of action potentials during the interburst interval and an earlier
onset of inspiratory bursts after Ih current
blockade. However, hyperpolarizing current pulses evoked only in a
small proportion of inspiratory neurons (0% of type I; 29% of type II
neurons) a depolarizing sag. Most of the neurons expressing an
Ih current (86%) were pacemaker neurons, which continued to generate rhythmic bursts after inactivating the
respiratory network pharmacologically with CNQX alone or with CNQX,
AP-5, strychnine, bicuculline, and carbenoxolone. Cs and ZD 7288 increased the frequency of pacemaker bursts and decreased the frequency
of action potentials between pacemaker bursts. Our findings suggest
that the Ih current plays an important role
in modulating respiratory frequency, which is presumably mediated by
pacemaker neurons.
Key words:
Ih current; cesium; ZD 7288; rhythm
generation; brainstem; respiratory neurons; mammals; mouse
Copyright © 2000 Society for Neuroscience 0270-6474/00/2082994-12$05.00/0
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