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The Journal of Neuroscience, January 9, 2008, 28(2):519-528; doi:10.1523/JNEUROSCI.3666-07.2008

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Behavioral/Systems/Cognitive
4* Nicotinic Receptors in preBötzinger Complex Mediate Cholinergic/Nicotinic Modulation of Respiratory Rhythm

Xuesi M. Shao,¹ Wenbin Tan,¹ Joanne Xiu,² Nyssa Puskar,² Carlos Fonck,² Henry A. Lester,² and Jack L. Feldman¹

¹Department of Neurobiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095-1763, and ²Division of Biology, California Institute of Technology, Pasadena, California 91125

Correspondence should be addressed to Xuesi M. Shao, Department of Neurobiology, David Geffen School of Medicine at University of California, Los Angeles, Box 951763, Los Angeles, CA 90095-1763. Email: mshao{at}ucla.edu

Acetylcholine and nicotine can modulate respiratory patterns by acting on nicotinic acetylcholine receptors (nAChRs) in the preBötzinger complex (preBötC). To further explore the molecular composition of these nAChRs, we studied a knock-in mouse strain with a leucine-to-alanine mutation in the M2 pore-lining region (L9'A) of the nAChR 4 subunit; this mutation renders 4-containing receptors hypersensitive to agonists. We recorded respiratory-related rhythmic motor activity from hypoglossal nerve (XIIn) and patch-clamped preBötC inspiratory neurons in an in vitro medullary slice preparation from neonatal mice. Nicotine affected respiratory rhythm at concentrations 100-fold lower in the homozygous L9'A knock-in mice compared with wild-type mice. Bath application of 5 nM nicotine increased the excitability of preBötC inspiratory neurons, increased respiratory frequency, and induced tonic/seizure-like activities in XIIn in L9'A mice, effects similar to those induced by 1 µM nicotine in wild-type mice. In L9'A mice, microinjection of low nanomolar concentrations of nicotine into the preBötC increased respiratory frequency, whereas injection into the ipsilateral hypoglossal (XII) nucleus induced tonic/seizure-like activity. The 4*-selective nAChR antagonist dihydro-β-erythroidine produced opposite effects and blocked the nicotinic responses. These data, showing that nAChRs in the preBötC and XII nucleus in L9'A mice are hypersensitive to nicotine and endogenous ACh, suggest that functional 4* nAChRs are present in the preBötC. They mediate cholinergic/nicotinic modulation of the excitability of preBötC inspiratory neurons and of respiratory rhythm. Furthermore, functional 4* nAChRs are present in XII nucleus and mediate cholinergic/nicotinic modulation of tonic activity in XIIn.

Key words: L9'A knock-in mice; 4 subunit; preBötzinger complex; inspiratory neurons; hypoglossal nucleus; nicotine

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Received May 11, 2007; revised Dec. 4, 2007; accepted Dec. 4, 2007.

Correspondence should be addressed to Xuesi M. Shao, Department of Neurobiology, David Geffen School of Medicine at University of California, Los Angeles, Box 951763, Los Angeles, CA 90095-1763. Email: mshao{at}ucla.edu

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