Enhanced phrenic long‐term facilitation (pLTF) following intermittent hypoxia in a rat ALS model (SOD1G93A) is attenuated by spinal siRNAs targeting BDNF and TrkB synthesis

Abstract

Acute intermittent hypoxia (AIH; 3, 5-min episodes, 11% O2) elicits a serotonin and BDNF-synthesis dependentform of respiratory plasticity known as pLTF. pLTF is enhanced at disease end-stage in SOD1G93A (106%) versus wild-type rats (42%; Nichols et al., 2010). The mechanism of this enhancement is unknown. The BDNF synthesis-dependent pathway to pLTF is induced by Gq coupled metabotropic 5-HT2 receptors. Other pathways can elicit phrenic motor facilitation, including activation of Gs protein-coupled metabotropic receptors (eg. 5-HT7 and A2A); this mechanism requires new synthesis of immature TrkB isoforms. We hypothesized that enhanced pLTF at ALS disease end-stage is the result of contributions from both pathways and would therefore require both BDNF and TrkB synthesis. AIH-induced pLTF was studied in anesthetized, paralyzed and ventilated SOD1G93A rats ~2 hours after intrathecal delivery of siRNAs targeting BDNF or TrkB mRNA. siBDNF attenuated pLTF to ~20% in wild-type (n = 6; p < 0.05) and SOD1G93A rats (n = 3; p < 0.05). In contrast, siTrkB had no effect on pLTF in wild-type rats (n = 5), but attenuated pLTF (~60%) in SOD1G93A rats (n = 3; p < 0.05). Thus, both Gs and Gq pathways contribute to enhanced pLTF in SOD1G93A rats. This project increases our understanding of respiratory plasticity and metaplasticity, and has important implications for the control of breathing in neurodegenerative diseases. [Supported by NIH NS057778 and T32 HL007654]