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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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