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The Journal of Neuroscience, August 25, 2004, 24(34):7549-7556; doi:10.1523/JNEUROSCI.1871-04.2004
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Behavioral/Systems/Cognitive
Substance P-Mediated Modulation of Pacemaker Properties in the Mammalian Respiratory Network
Fernando Peña1,2 andJan-Marino Ramirez1 1Department of Organismal Biology and Anatomy, The University of Chicago, Chicago, Illinois 60637, and 2Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, 14330 México Distrito Federal, México
Neuromodulators are integral parts of a neuronal network, and unraveling how these substances alter neuronal activity is critical for understanding how networks generate patterned activity and, ultimately, behavior. In this study, we examined the cellular mechanisms underlying the excitatory action of substance P (SP) on the respiratory network isolated in spontaneously active transverse slice preparation of mice. SP produced a slow depolarization in all recorded inspiratory pacemaker and non-pacemaker neurons. Ion exchange experiments and blockers for different ion channels suggest that the slow depolarization is caused by the activation of a low-threshold TTX-insensitive cationic current that carries mostly Na+. The SP-induced slow depolarization increased tonic discharge in non-pacemaker neurons and primarily enhanced the frequency of bursting in Cd2+-insensitive pacemaker neurons. In the Cd2+-sensitive pacemaker neuron, the burst frequency was not significantly affected, whereas burst duration and amplitude were more enhanced than in Cd2+-insensitive pacemaker neurons. In a subset of non-pacemaker neurons that produced NMDA-dependent subthreshold oscillations, SP caused the production of bursts of action potentials. We conclude that the degree of pacemaker activity in the respiratory network is not fixed but dynamically regulated by neuromodulators such as SP. This finding may have clinical implications for Rett syndrome in which SP levels along with other neuromodulators are decreased in the brainstem.
Key words: respiratory network; pacemaker neurons; TTX-resistant Na+ current; substance P; neuromodulation; bursting properties
Received May 13, 2004; revised July 21, 2004; accepted July 21, 2004.
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