Spinal NMDA receptor activation is necessary to initiate but not maintain ampakine-hypoxia induced phrenic motor facilitation

Abstract

Ampakines are a class of compounds which act as positive allosteric modulators of AMPA receptors. Intravenous (i.v.) delivery of a “low impact” ampakine prior to a single brief hypoxic episode produces a persistent (≥60 min) increase in phrenic nerve output (i.e., phrenic motor facilitation, pMF) (Thakre et al., J. Neurophysiol., 2021). Many forms of synaptic plasticity require an interplay of AMPA and NMDA receptors, including hippocampal long-term potentiation and acute intermittent hypoxia (AIH) induced long-term facilitation (LTF) in the phrenic motor system. Here, we tested the hypothesis that spinal NMDA receptor activation is necessary for pMF induced by a combination of ampakine and a single brief hypoxic episode (A+H). Phrenic nerve recordings were made from an experimental preparation that enables rigorous arterial blood gas control: urethane-anesthetized, ventilated, paralyzed and vagotomized adult male Sprague-Dawley rats. Ampakine CX717 (15 mg/kg, i.v.) was delivered 2-min prior to a 5-min hypoxic episode (partial pressure of arterial O2 ~40 mmHg). In experiment 1, the NMDA receptor antagonist MK-801 (10 μM) or vehicle (physiological saline) was intrathecally delivered at spinal segment C4 prior to A+H. Vehicle treated rats demonstrated greater phrenic burst amplitude at 60-min post-hypoxia (burst amplitude = 47±1 %BL) versus MK-801 treated rats (11±1 %BL; 2-way repeated measures analysis of variance, RM ANOVA, treatment effect, P=0.02, n=5 per group). In experiment 2, intrathecal MK-801 or vehicle (n=5 per group) were delivered 20-min after A+H. Neither MK-801 nor vehicle impacted pMF magnitude (2-way RM ANOVA, treatment effect, P=0.6). We conclude that the induction, but not maintenance, of A+H-induced pMF requires spinal NMDA receptor activation in contrast with AIH-induced phrenic long-term facilitation, which requires NMDA receptor activation for its maintenance (but not initiation). We reveal a novel mechanism of phrenic motor plasticity akin to hippocampal activity-induced synaptic plasticity, which requires NMDA receptor activation for initiation, but not maintenance. We suggest that ampakine pretreatment may have value in boosting the therapeutic impact of hypoxia-based neurorehabilitation strategies (Gonzalez-Rothi et al., J. Appl. Physiol., 2015). R01 HL139708 02 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.