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© 2019 Picardo et al. Inspiratory breathing movements depend on pre-Bötzinger complex (preBötC) interneurons that express calcium (Ca 2+ )-activated nonselective cationic current (I CAN ) to generate robust neural bursts. Hypothesized to be rhythmogenic, reducing I CAN is predicted to slow down or stop breathing; its contributions to motor pattern would be reflected in the magnitude of movements (output). We tested the role(s) of I CAN using reverse genetic techniques to diminish its putative ion channels Trpm4 or Trpc3 in preBötC neurons in vivo. Adult mice transduced with Trpm4-targeted short hairpin RNA (shRNA) progressively decreased the tidal volume of breaths yet surprisingly increased breathing frequency, often followed by gasping and fatal respiratory failure. Mice transduced with Trpc3-targeted shRNA survived with no changes in breathing. Patch-clamp and field recordings from the preBötC in mouse slices also showed an increase in the frequency and a decrease in the magnitude of pre-BötC neural bursts in the presence of Trpm4 antagonist 9-phenanthrol, whereas the Trpc3 antagonist pyrazole-3 (pyr-3) showed inconsistent effects on magnitude and no effect on frequency. These data suggest that Trpm4 mediates I CAN , whose influence on frequency contradicts a direct role in rhythm generation. We conclude that Trpm4-mediated I CAN is indispensable for motor output but not the rhythmogenic core mechanism of the breathing central pattern generator.

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PLoS Biology