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The Journal of Neuroscience, December 19, 2007, 27(51):14128-14138; doi:10.1523/JNEUROSCI.4167-07.2007

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Behavioral/Systems/Cognitive
Serotonergic Neurons Activate Chemosensitive Retrotrapezoid Nucleus Neurons by a pH-Independent Mechanism

Daniel K. Mulkey,¹ Diane L. Rosin,¹ Gavin West,¹ Ana C. Takakura,^1,2 Thiago S. Moreira,^1,2 Douglas A. Bayliss,¹ and Patrice G. Guyenet¹

¹Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, and ²Department of Physiology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP 04023-060, Brazil

Correspondence should be addressed to Daniel K. Mulkey, Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, Unit 3156, Storrs-Mansfield, CT 06269-9011. Email: daniel.mulkey{at}uconn.edu

Serotonin activates respiration and enhances the stimulatory effect of CO₂ on breathing. The present study tests whether the mechanism involves the retrotrapezoid nucleus (RTN), a group of medullary glutamatergic neurons activated by extracellular brain pH and presumed to regulate breathing. We show that the RTN is innervated by both medullary and pontine raphe and receives inputs from thyrotropin-releasing hormone (TRH) and substance P-expressing neurons. Coexistence of serotonin and substance P in terminals within RTN confirmed that lower medullary serotonergic neurons innervate RTN. In vivo, unilateral injection of serotonin into RTN stimulated inspiratory motor activity, and pH-sensitive RTN neurons were activated by iontophoretic application of serotonin or substance P. In brain slices, pH-sensitive RTN neurons were activated by serotonin, substance P, and TRH. The effect of serotonin in slices was ketanserin sensitive and persisted in the presence of glutamate, GABA, glycine, and purinergic ionotropic receptor antagonists. Serotonin and pH had approximately additive effects on the discharge rate of RTN neurons, both in slices and in vivo. In slices, serotonin produced an inward current with little effect on conductance and had no effect on the pH-induced current. We conclude that (1) RTN receives input from multiple raphe nuclei, (2) serotonin, substance P, and TRH activate RTN chemoreceptors, and (3) excitatory effects of serotonin and pH are mediated by distinct ionic conductances. Thus, RTN neurons presumably contribute to the respiratory stimulation caused by serotonergic neurons, but serotonin seems without effect on the cellular mechanism by which RTN neurons detect pH.

Key words: chemosensitivity; raphe; central respiratory control; ventral medullary surface; pH signaling; brain slice

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Received Sept. 11, 2007; revised Nov. 10, 2007; accepted Nov. 10, 2007.

Correspondence should be addressed to Daniel K. Mulkey, Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, Unit 3156, Storrs-Mansfield, CT 06269-9011. Email: daniel.mulkey{at}uconn.edu

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