N-Methyl-D-aspartate receptor (NMDAR) activity in the nucleus tractus solitarii (nTS) is required for the full expression of phrenic long-term facilitation after acute intermittent hypoxia

Abstract

Exposure to acute intermittent hypoxia (AIH) induces a persistent elevation of phrenic nerve activity during the normoxic period, or phrenic long-term facilitation (pLTF). We have previously shown that nTS activity is necessary for both the development and maintenance of pLTF. However, the underlying cellular mechanisms and pathways are not yet clear. Hypoxia induces the release of glutamate from chemoafferents in the nTS, where it binds to AMPA and NMDA receptors. Previous studies have shown that activation of NMDARs increases neuronal calcium influx and triggers long-term potentiation. The present study aimed to test the role of NMDARs in pLTF and, in particular, to determine whether activation of these receptors in the nTS is required for hypoxia-induced pLTF. Mean arterial pressure (MAP) and splanchnic sympathetic and phrenic nerve activity (sSNA and PhrNA) were recorded in anesthetized, vagotomized, neuromuscularly blocked, and artificially ventilated male Sprague-Dawley rats. Animals were exposed to 10 bouts of 10% O2 (45 sec, every 5 min; AIH). Time controls (TC) were exposed to a single hypoxia bout. Parameters were measured for an additional 1 hour after the end of AIH and compared to their initial baseline (Bsl) values or TC. The NMDAR antagonist MK-801 (3 mg kg (-1), i.v.) was injected systemically, or AP5 (10 mM, 60 nl) nanoinjected bilaterally into the nTS, after the development of AIH-induced pLTF. To test whether induction of AIH or blockade of NMDARs alters neuronal function of the nTS, nTS neuronal Ca2+ responses to AIH and MK-801 were measured by fiber photometry in 3 rats previously nanoinjected with a Ca2+ indicator GCaMP-expressing virus in the nTS. Minute PhrNA (MinPhrNA, frequency x amplitude) increased 1hr after AIH (% of Bsl, 438 ± 184%; mean ± SE; p <0.01; t-test) and was significantly greater than TC (74 ± 15%Bsl p <0.01; t-test), indicating pLTF. AIH also increased nTS neuronal Ca2+. Systemic blockade of NMDARs after the development of pLTF decreased MAP, sSNA, and nTS Ca2+ and eliminated pLTF, consistent with others. Bilateral nTS nanoinjection of AP5 reduced but did not abolish pLTF (before AP5: 449 ± 109% vs. after AP5: 371 ± 107%Bsl; p <0.05; paired t-test), increased sSNA (before AP5: 192 ± 31% vs. after AP5: 219 ± 42%; p= 0.08; paired t-test) but did not alter MAP. nTS AP5 after TC had no effect on MAP, MinPhrNA (before AP5: 99 ± 46% vs. after AP5: 103 ± 43%; p = 0.44; t-test) or sSNA (before AP5: 244 ± 92% vs. after AP5: 245 ± 81%; =0.94; paired t-test). Altogether, these results show that systemic blockade of NMDARs eliminates pLTF, and our data suggest that nTS NMDARs are critical components for the maintenance of AIH-induced neuroplasticity. R01-HL-98602. This is the full abstract presented at the American Physiology Summit 2024 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.