Formation and maintenance of ventilatory long-term facilitation require NMDA but not non-NMDA receptors in awake rats

Abstract

N-methyl-d-aspartate (NMDA) receptor antagonism in the phrenic motonucleus area eliminates phrenic long-term facilitation (pLTF; a persistent augmentation of phrenic nerve activity after episodic hypoxia) in anesthetized rats. However, whether NMDA antagonism can eliminate ventilatory LTF (vLTF) in awake rats is unclear. The role of non-NMDA receptors in LTF is also unknown. Serotonin receptor antagonism before, but not after, episodic hypoxia eliminates pLTF, suggesting that serotonin receptors are required for induction, but not maintenance, of pLTF. However, because NMDA and non-NMDA ionotropic glutamate receptors are directly involved in mediating the inspiratory drive to phrenic, hypoglossal, and intercostal motoneurons, we hypothesized that these receptors are required for both formation and maintenance of vLTF. vLTF, induced by five episodes of 5-min poikilocapnic hypoxia (10% O(2)) with 5-min normoxia intervals, was measured with plethysmography in conscious adult male Sprague-Dawley rats. Either (+/-)-2-amino-5-phosphonovaleric acid (APV; NMDA antagonist, 1.5 mg/kg) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; non-NMDA antagonist, 10 mg/kg) was systemically (ip) injected approximately 30 min before hypoxia. APV was also injected immediately after or 20 min after episodic hypoxia in additional groups. As control, vehicle was similarly injected in each rat 1-2 days before. Regardless of being injected before or after episodic hypoxia, vehicle did not alter vLTF ( approximately 23%), whereas APV eliminated vLTF while having little effect on baseline ventilation or hypoxic ventilatory response. In contrast, CNQX enhanced vLTF ( approximately 34%) while decreasing baseline ventilation. Collectively, these results suggest that activation of NMDA but not non-NMDA receptors is necessary for formation and maintenance of vLTF in awake rats.

Does Trans-Spinal Direct Current Stimulation Alter Phrenic Motoneurons and Respiratory Neuromechanical Outputs in Humans? A Double-Blind, Sham-Controlled, Randomized, Crossover Study

“…For these reasons, DC stimulation-induced aftereffects are thought to arise from synaptic changes via long-term potentiation-/ depression-like processes as well as nonsynaptic mechanisms involving changes in neural membrane function (Ardolino et al, 2005). In the light of our results and based on our current understanding of tsDCS mechanisms , it is conceivable that the mechanisms underlying enhanced DiMEPs after tsDCS could also involve changes in neurotransmission, which would be in line with the fact that (1) glutamate drives the pathway to PMNs during inspiration (McCrimmon et al, 1989;Chitravanshi and Sapru, 1996) and modulates synaptic strength in the short and long term via NMDA receptors (Rekling et al, 2000;McGuire et al, 2008); (2) GABA is intimately involved in respiratory motor control, as PMNs are inhibited by GABA A receptors during the expiratory phase of respiration (Fedorko et al, 1983;Merrill and Fedorko, 1984); and, (3) PMN NMDA receptors also contribute to excitatory neurotransmission (Chitravanshi and Sapru, 1996) and are implicated in many models of plasticity including phrenic LTF (Golder, 2009). This idea is also supported by recent arguments from animal studies: (1) both anodal and cathodal tsDCS increased glutamate analog D-2,3-3 H-aspartic acid release in vitro (Ahmed and Wieraszko, 2012), and (2) it has been proposed that cathodal tsDCS may act by directly inhibiting the spinal GABAergic system or by exerting overexcitation of postsynaptic neurons (Ahmed, 2013) likely through increased glutamate release (Ahmed and Wieraszko, 2012).…”

“…PMNs, located in C3-C5 cervical spinal segments (Verin et al, 2011), are the site of interactions between various sources of the respiratory motor output (Aminoff and Sears, 1971) and are most likely instrumental to the interplay between bulbospinal and corticospinal respiratory drive that characterizes human respiratory control (Murphy et al, 1990;Davey et al, 1996;Mehiri et al, 2006). Since persistent changes in synaptic inputs to PMNs have been proposed as a key mechanism underlying vLTF in physiological conditions, we hypothesized that noninvasive stimulation could be used to artificially promote spinal respiratory neuroplasticity.…”

Phrenic Motoneuron Discharge Patterns During Hypoxia-Induced Short-Term Potentiation in Rats

“…The potential impact of urethane anesthesia on STP is not certain. However, respiratory STP occurs in both anesthetized animals (e.g., current data; Golder et al 2005;Hayashi et al 1993) and conscious humans (Fregosi 1991) and animals (Kline et al 2002;McGuire 2008). Urethane was selected as the anesthetic in this study because robust hypoxic phrenic responses occur in urethane anesthetized rats (Bach and Mitchell 1996;Baker-Herman et al 2004).…”

Functional recovery after cervical spinal cord injury: Role of neurotrophin and glutamatergic signaling in phrenic motoneurons

“…Serotonergic pathways play a key role in phrenic motor plasticity and recovery from SCI (Basura et al, 2001; Fuller et al, 2005; Hadley et al, 1999; Zhou et al, 2001). Glutamatergic pathways are also essential in the neuroplasticity of phrenic motoneuron output (Alilain and Goshgarian, 2008; McGuire et al, 2008). After SH, 5-HTR and NMDA receptor expression increases within phrenic motoneurons, and the time course of these changes corresponds with the return of spontaneous recovery of rhythmic ipsilateral DIAm activity (Mantilla et al, 2012).…”