Acute intermittent hypoxia (AIH) initiates plasticity in the phrenic motor system, specifically phrenic Long Term Facilitation (pLTF). pLTF requires spinal serotonin receptor activation (5-HT2A), new synthesis of brain derived neurotrophic factor (BDNF) (Baker-Herman et al., Nature Neurosci., 2004), activation of its high affinity receptor, TrkB, and downstream signaling, presumably through activation of MAP kinases (extracellular regulated kinases, ERK 1/2) and/or protein kinase B (Akt). Since respiratory LTF is enhanced by repetitive intermittent hypoxia (Wilkerson et al., ibid, 2005; Ling et al., J. Neurosci., 2001), we hypothesized that exposure to AIH for 8-10 weeks (3x per week) would enhance expression of cellular and synaptic proteins associated with pLTF, thus representing a potential mechanism for enhanced LTF following chronic intermittent hypoxia exposures. Using immunohistochemical staining in C4 spinal sections, we found that pretreatment with thrice weekly AIH increased the expression of each of these proteins (5-HT2A, BDNF, TrkB, pERK/ERK and pAkt/Akt) in presumptive phrenic motoneurons. Activation of astrocytes (GFAP positive cells) or microglia (OX-42 positive cells) was not observed, suggesting that modest protocols of chronic intermittent hypoxia do not trigger reactive gliosis. In conclusion, thrice-weekly AIH enhances respiratory proteins that underlie pLTF, possibly contributing to enhanced respiratory LTF following chronic intermittent hypoxia. (NIH HL80209).