Respiratory Physiology & Neurobiology 147 (2005) 19–30 An astrocyte toxin influences the pattern of breathing and the ventilatory response to hypercapnia in neonatal rats John K. Young a , Ismail A. Dreshaj b , Christopher G. Wilson b , Richard J. Martin b , Syed I.A. Zaidi a , Musa A. Haxhiu a,b,∗ a Department of Anatomy, Howard University College of Medicine, Washington, DC 20059, USA b Department of Pediatrics, University Hospitals of Cleveland Case Western Reserve University, Cleveland, OH 44106, USA Received 7 December 2004; received in revised form 18 January 2005; accepted 31 January 2005 Abstract Recent in vitro data suggest that astrocytes may modulate respiration. To examine this question in vivo, we treated 5-day- old rat pups with methionine sulfoximine (MS), a compound that alters carbohydrate and glutamate metabolism in astrocytes, but not neurons. MS-treated pups displayed a reduced breathing frequency (f) in baseline conditions relative to saline-treated pups. Hypercapnia (5% CO 2 ) increased f in both groups, but f still remained significantly lower in the MS-treated group. No differences between treatment groups in the responses to hypoxia (8% O 2 ) were observed. Also, MS-treated rats showed an enhanced accumulation of glycogen in neurons of the facial nucleus, the nucleus ambiguus, and the hypoglossal nucleus, structures that regulate respiratory activity and airway patency. An altered transfer of nutrient molecules from astrocytes to neurons may underlie these effects of MS, although direct effects of MS upon neurons or upon peripheral structures that regulate respiration cannot be completely ruled out as an explanation. © 2005 Elsevier B.V. All rights reserved. Keywords: Glia; Ventrolateral medulla; Glycogen; Respiratory rate; Methionine sulfoximine 1. Introduction Hypercapnia is thought to exert its effects on ventilation mainly through activation of discrete ∗ Corresponding author. Present address: Department of Physi- ology, Howard University Specialized Neuroscience Research Pro- gram, College of Medicine, 520 W St., NW, Washington, DC 20059, USA. Tel.: +1 202 806 6330; fax: +1 202 806 4479. E-mail address: jyoung@howard.edu (J.K. Young). chemosensitive cell groups within the medulla ob- longata (Coates et al., 1993; Richerson, 2004). These effects are mediated partly via alterations in extracellu- lar and intracellular pH (Ballantyne and Scheid, 2001). Proteins that regulate pH are present on both astrocytes and neurons, and include Na/HCO 3 co-transporters and a family of Na/H exchanger proteins (Baird et al., 1999; Makara et al., 2001; Schmitt et al., 2000). Thus, glia cells may participate in the regulation of the ventilatory response to hypercapnia. 1569-9048/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2005.01.009