Spinal NMDA receptor activation constrains inactivity-induced phrenic motor 1

40 Reduced spinal synaptic inputs to phrenic motor neurons elicit a unique form of spinal 41 plasticity known as inactivity-induced phrenic motor facilitation (iPMF). iPMF requires 42 TNFα and atypical protein kinase C (aPKC) activity within spinal segments containing 43 the phrenic motor nucleus to stabilize early, transient increases in phrenic burst 44 amplitude into long-lasting iPMF. Here, we tested the hypothesis that spinal NMDA 45 receptor (NMDAR) activation constrains long-lasting iPMF in some rat substrains. 46 Phrenic motor output was recorded in anesthetized, ventilated Harlan (HSD) and 47 Charles River (CRSD) Sprague Dawley rats exposed to a 30 min central neural apnea. 48 HSD rats expressed a robust, long-lasting (>60 min) increase in phrenic burst amplitude 49 (i.e., long-lasting iPMF) when respiratory neural activity was restored. By contrast, 50 CRSD rats expressed an attenuated, transient (~15 min) iPMF. Spinal NMDAR 51 inhibition with APV before neural apnea or shortly (4 min) prior to the resumption of 52 respiratory neural activity revealed long-lasting iPMF in CRSD that was phenotypically 53 similar to HSD. By constrast, APV did not alter iPMF expression in HSD rats. Spinal 54 TNFα or aPKC inhibition impaired long-lasting iPMF enabled by NMDAR inhibition in 55 CRSD, suggesting similar mechanisms give rise to long-lasting iPMF in CRSD with 56 NMDAR inhibition as those giving rise to long-lasting iPMF in HSD rats. These results 57 suggest that NMDAR can impose constraints on TNFα-induced aPKC activation after 58 neural apnea, impairing stabilization of transient iPMF into long-lasting iPMF. These 59 data may have important implications for understanding differential responses to 60 reduced respiratory neural activity in a heterogenous human population. 6