Glutamate receptor plasticity in brainstem respiratory nuclei following chronic hypercapnia in goats

Patients that retain CO (2) in 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. We recently characterized the time‐dependent physiologic effects of chronic hypercapnia in goats, which suggested potential neuroplastic shifts in ventilatory control mechanisms. However, little is known about how chronic hypercapnia affects brainstem respiratory nuclei (BRN) that control multiple physiologic functions including breathing. Since many CNS neuroplastic mechanisms include changes in glutamate (AMPA (GluR) and NMDA (GluN)) receptor expression and/or phosphorylation state to modulate synaptic strength and network excitability, herein we tested the hypothesis that changes occur in glutamatergic signaling within BRN during chronically elevated inspired CO (2) (InCO (2))‐hypercapnia. Healthy goats were euthanized after either 24 h or 30 days of chronic exposure to 6% InCO (2) or room air, and brainstems were rapidly extracted for western blot analyses to assess GluR and GluN receptor expression within BRN. Following 24‐hr exposure to 6% InCO (2), GluR or GluN receptor expression were changed from control (P < 0.05) in the solitary complex (NTS & DMV),ventrolateral medulla (VLM), medullary raphe (MR), ventral respiratory column (VRC), hypoglossal motor nucleus (HMN), and retrotrapezoid nucleus (RTN). These neuroplastic changes were not found following 30 days of chronic hypercapnia. However, at 30 days of chronic hypercapnia, there was overall increased (P < 0.05) expression of glutamate receptors in the VRC and RTN. We conclude that time‐ and site‐specific glutamate receptor neuroplasticity may contribute to the concomitant physiologic changes that occur during chronic hypercapnia.