Impact of glutamatergic and serotonergic neurotransmission on diaphragm muscle activity after cervical spinal hemisection

Carlos Bernardo Mantilla, Heather M. Gransee, Wen Zhi Zhan, Gary C Sieck

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Incomplete cervical spinal cord hemisection at C2 (SH) disrupts descending excitatory drive to phrenic motoneurons, paralyzing the ipsilateral diaphragm muscle. Spontaneous recovery over time is associated with increased phrenic motoneuron expression of glutamatergic N-methyl-D-aspartate (NMDA) and serotonergic 5-HT2A receptors. We hypothesized that NMDA and 5-HT2A receptor-mediated neurotransmission play a role in ipsilateral diaphragm muscle activity post-SH. Adult male Sprague-Dawley rats were implanted with bilateral diaphragm EMG electrodes for chronic EMG recordings up to 28 days post-SH (SH 28D). The extent of recovery was calculated by peak root-mean-square (RMS) EMG amplitude. In all animals, absence of ipsilateral activity was verified at 3 days post-SH. Diaphragm EMG activity was also recorded during exposure to hypoxia-hypercapnia (10% O2-5% CO2). In SH animals displaying recovery of ipsilateral diaphragm EMG activity at SH 28D, cervical spinal cord segments containing the phrenic motor nucleus (C3-C5) were surgically exposed and either the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (D-AP5; 100 mM, 30 µl) or 5-HT2A receptor antagonist ketanserin (40 mM, 30 µl) was instilled intrathecally. Following D-AP5, diaphragm EMG amplitude was reduced ipsilaterally, during both eupnea (42% of pre-D-AP5 value; P = 0.007) and hypoxia-hypercapnia (31% of pre-D-AP5 value; P = 0.015), with no effect on contralateral EMG activity or in uninjured controls. Treatment with ketanserin did not change ipsilateral or contralateral RMS EMG amplitude in SH animals displaying recovery at SH 28D. Our results suggest that spinal glutamatergic NMDA receptor-mediated neurotransmission plays an important role in ipsilateral diaphragm muscle activity after cervical spinal cord injury. NEW & NOTEWORTHY Spontaneous recovery following C2 spinal hemisection (SH) is associated with increased phrenic motoneuron expression of glutamatergic and serotonergic receptors. In this study, we show that pharmacological inhibition of glutamatergic N-methyl- D-aspartate (NMDA) receptors blunts ipsilateral diaphragm activity post-SH. In contrast, pharmacological inhibition of serotonergic 5-HT2A receptors does not change diaphragm EMG activity post-SH. Our results suggest that NMDA receptor-mediated glutamatergic neurotransmission plays an important role in enhancing rhythmic respiratory-related diaphragm activity after spinal cord injury.

Original languageEnglish (US)
Pages (from-to)1732-1738
Number of pages7
JournalJournal of Neurophysiology
Volume118
Issue number3
DOIs
StatePublished - Sep 5 2017

Fingerprint

Diaphragm
Synaptic Transmission
Muscles
Receptor, Serotonin, 5-HT2A
N-Methyl-D-Aspartate Receptors
Motor Neurons
Ketanserin
Hypercapnia
N-Methylaspartate
Spinal Cord Injuries
Pharmacology
Serotonin 5-HT2 Receptor Antagonists
2-Amino-5-phosphonovalerate
Sprague Dawley Rats
Electrodes

Keywords

  • D-AP5
  • Ketanserin
  • Neurotransmitter
  • Respiration
  • Spinal cord injury

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology

Cite this

Impact of glutamatergic and serotonergic neurotransmission on diaphragm muscle activity after cervical spinal hemisection. / Mantilla, Carlos Bernardo; Gransee, Heather M.; Zhan, Wen Zhi; Sieck, Gary C.

In: Journal of Neurophysiology, Vol. 118, No. 3, 05.09.2017, p. 1732-1738.

Research output: Contribution to journalArticle

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N2 - Incomplete cervical spinal cord hemisection at C2 (SH) disrupts descending excitatory drive to phrenic motoneurons, paralyzing the ipsilateral diaphragm muscle. Spontaneous recovery over time is associated with increased phrenic motoneuron expression of glutamatergic N-methyl-D-aspartate (NMDA) and serotonergic 5-HT2A receptors. We hypothesized that NMDA and 5-HT2A receptor-mediated neurotransmission play a role in ipsilateral diaphragm muscle activity post-SH. Adult male Sprague-Dawley rats were implanted with bilateral diaphragm EMG electrodes for chronic EMG recordings up to 28 days post-SH (SH 28D). The extent of recovery was calculated by peak root-mean-square (RMS) EMG amplitude. In all animals, absence of ipsilateral activity was verified at 3 days post-SH. Diaphragm EMG activity was also recorded during exposure to hypoxia-hypercapnia (10% O2-5% CO2). In SH animals displaying recovery of ipsilateral diaphragm EMG activity at SH 28D, cervical spinal cord segments containing the phrenic motor nucleus (C3-C5) were surgically exposed and either the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (D-AP5; 100 mM, 30 µl) or 5-HT2A receptor antagonist ketanserin (40 mM, 30 µl) was instilled intrathecally. Following D-AP5, diaphragm EMG amplitude was reduced ipsilaterally, during both eupnea (42% of pre-D-AP5 value; P = 0.007) and hypoxia-hypercapnia (31% of pre-D-AP5 value; P = 0.015), with no effect on contralateral EMG activity or in uninjured controls. Treatment with ketanserin did not change ipsilateral or contralateral RMS EMG amplitude in SH animals displaying recovery at SH 28D. Our results suggest that spinal glutamatergic NMDA receptor-mediated neurotransmission plays an important role in ipsilateral diaphragm muscle activity after cervical spinal cord injury. NEW & NOTEWORTHY Spontaneous recovery following C2 spinal hemisection (SH) is associated with increased phrenic motoneuron expression of glutamatergic and serotonergic receptors. In this study, we show that pharmacological inhibition of glutamatergic N-methyl- D-aspartate (NMDA) receptors blunts ipsilateral diaphragm activity post-SH. In contrast, pharmacological inhibition of serotonergic 5-HT2A receptors does not change diaphragm EMG activity post-SH. Our results suggest that NMDA receptor-mediated glutamatergic neurotransmission plays an important role in enhancing rhythmic respiratory-related diaphragm activity after spinal cord injury.

AB - Incomplete cervical spinal cord hemisection at C2 (SH) disrupts descending excitatory drive to phrenic motoneurons, paralyzing the ipsilateral diaphragm muscle. Spontaneous recovery over time is associated with increased phrenic motoneuron expression of glutamatergic N-methyl-D-aspartate (NMDA) and serotonergic 5-HT2A receptors. We hypothesized that NMDA and 5-HT2A receptor-mediated neurotransmission play a role in ipsilateral diaphragm muscle activity post-SH. Adult male Sprague-Dawley rats were implanted with bilateral diaphragm EMG electrodes for chronic EMG recordings up to 28 days post-SH (SH 28D). The extent of recovery was calculated by peak root-mean-square (RMS) EMG amplitude. In all animals, absence of ipsilateral activity was verified at 3 days post-SH. Diaphragm EMG activity was also recorded during exposure to hypoxia-hypercapnia (10% O2-5% CO2). In SH animals displaying recovery of ipsilateral diaphragm EMG activity at SH 28D, cervical spinal cord segments containing the phrenic motor nucleus (C3-C5) were surgically exposed and either the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (D-AP5; 100 mM, 30 µl) or 5-HT2A receptor antagonist ketanserin (40 mM, 30 µl) was instilled intrathecally. Following D-AP5, diaphragm EMG amplitude was reduced ipsilaterally, during both eupnea (42% of pre-D-AP5 value; P = 0.007) and hypoxia-hypercapnia (31% of pre-D-AP5 value; P = 0.015), with no effect on contralateral EMG activity or in uninjured controls. Treatment with ketanserin did not change ipsilateral or contralateral RMS EMG amplitude in SH animals displaying recovery at SH 28D. Our results suggest that spinal glutamatergic NMDA receptor-mediated neurotransmission plays an important role in ipsilateral diaphragm muscle activity after cervical spinal cord injury. NEW & NOTEWORTHY Spontaneous recovery following C2 spinal hemisection (SH) is associated with increased phrenic motoneuron expression of glutamatergic and serotonergic receptors. In this study, we show that pharmacological inhibition of glutamatergic N-methyl- D-aspartate (NMDA) receptors blunts ipsilateral diaphragm activity post-SH. In contrast, pharmacological inhibition of serotonergic 5-HT2A receptors does not change diaphragm EMG activity post-SH. Our results suggest that NMDA receptor-mediated glutamatergic neurotransmission plays an important role in enhancing rhythmic respiratory-related diaphragm activity after spinal cord injury.

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KW - Respiration

KW - Spinal cord injury

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