Daily intermittent hypoxia augments spinal BDNF levels, ERK phosphorylation and respiratory long-term facilitation

Abstract

Acute intermittent hypoxia (AIH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). We hypothesized that: 1) daily AIH (dAIH) preconditioning enhances phrenic and hypoglossal (XII) LTF in a rat strain with low constitutive LTF expression; 2) dAIH induces brain-derived neurotrophic factor (BDNF), a critical protein for phrenic LTF (pLTF) in the cervical spinal cord; and 3) dAIH increases post-AIH extracellular regulated kinase (ERK) activation. Phrenic and XII motor output were monitored in anesthetized dAIH- or sham-treated Brown Norway rats with and without acute AIH. pLTF was observed in both sham (18±9% baseline; 60 min post-hypoxia; p<0.05; n=18) and dAIH treated rats (37±8%; p<0.05; n=14), but these values were not significantly different (p=0.13). XII LTF was not observed in sham-treated rats (4±5%), but was revealed in dAIH pretreated rats (48±18%; p<0.05). dAIH preconditioning increased basal ventral cervical BDNF protein levels (24±8%; p<0.05), but had no significant effect on ERK phosphorylation. AIH increased BDNF in sham (25±8%; p<0.05), but not dAIH-pretreated rats (−7±4%), and had complex effects on ERK phosphorylation (ERK2 increased in shams whereas ERK1 increased in dAIH-treated rats). Thus, dAIH elicits metaplasticity in LTF, revealing XII LTF in a rat strain with no constitutive XII LTF expression. Increased BDNF synthesis may no longer be necessary for phrenic LTF following dAIH preconditioning since BDNF concentration is already elevated.