Glutamate Receptor Plasticity in Brainstem Respiratory Nuclei Following Chronic Hypercapnia in Goats

Abstract

Patients that retain CO2 with respiratory diseases such as chronic obstructive pulmonary disease (COPD) have worse prognoses and higher mortality rates than those with equal impairment of lung function without hypercapnia. However, little is known about the effects of chronic hypercapnia on the neurochemical mechanisms controlling brainstem respiratory nuclei (BRN). Common mechanisms of neuroplasticity involve changes in glutamate receptor expression/phosphorylation to modulate synaptic strength and network excitability, driven by changes in both AMPA (GluR) and NMDA (GluN) glutamate receptors. Accordingly, herein we tested the hypothesis that changes occur in glutamatergic signaling within the BRN during exposure to chronically elevated inspired CO2 (InCO2) induced hypercapnia. Healthy goats were euthanized after either 24 hours or 30 days of chronic exposure to 6% InCO2 or room air. The brainstems were extracted for western blot analyses to assess GluR and GluN receptor expression and phosphorylation state within the BRN. Compared to room air control goats, the following significant (P<0.05) changes were found after 24 hours of exposure to chronic hypercapnia: 1) AMPA receptor expression was greater, and NMDA receptor expression lower within the rostral solitary complex. 2) NMDA receptor expression/phosphorylation and APMA receptor phosphorylation were lower within the rostral ventrolateral medulla (VLM), while AMPA receptor expression/phosphorylation were greater in the caudal VLM. 3) AMPA receptor expression/phosphorylation were lower within the rostral retrotrapezoid nucleus. And, 4) NMDA receptor expression was greater within the caudal Raphe nucleus. The data indicate that within 24 hours of chronic hypercapnia changes have occurred in four BRN in GluR/GluN signaling which may contribute to an attenuated CO2‐induced hyperpnea and attenuated CO2 chemoreflex between 1 and 24 hours of hypercapnia (J. Physiol. 2018). GluR/GluN changes found at 24 hours of hypercapnia had returned to control levels after 30 days of hypercapnia. However, compared to room air control goats, the following significant (P<0.05) changes were found following 30 days of hypercapnia: 1) NMDA receptor phosphorylation was greater in the caudal ventral respiratory column, and 2) AMPA receptor expression was greater in the caudal RTN. The changes in GluR/GluN signaling between 24 hours and 30 days of chronic InCO2 may contribute to a sustained hyperpnea and normalization of the CO2 chemoreflex at 30 days.Support or Funding Information‐Department of Veteran Affairs ‐NIH Grant 007852This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.