Glutamate receptors in the nucleus tractus solitarius contribute to ventilatory acclimatization to hypoxia in rat

Key points Ventilation increases more with chronic than acute hypoxia and does not return to control levels when normoxia is restored, indicating plasticity in the reflexes that control breathing. Glutamate is the primary excitatory neurotransmitter between arterial chemoreceptors that sense hypoxia and neural circuits that control breathing in the brainstem. We microinjected specific glutamate receptor antagonists into the brainstem of awake unrestrained rats and found NMDA-type glutamate receptors explain increased ventilatory sensitivity to hypoxia after chronic hypoxia. AMPA-type glutamate receptors mediate increased ventilatory drive in normoxia after chronic hypoxia, as well as increased ventilation in acute hypoxia after chronic hypoxia and in control conditions. Phosphorylation of AMPA and NMDA receptors is increased by chronic hypoxia. The results indicate that plasticity in different glutamate receptors have unique effects on the reflexes that control breathing in chronic hypoxia and may share cellular mechanisms with other models of neural plasticity. Abstract When exposed to a hypoxic environment the body's first response is a reflex increase in ventilation, termed the hypoxic ventilatory response (HVR). With chronic sustained hypoxia (CSH), such as during acclimatization to high altitude, an additional time-dependent increase in ventilation occurs, which increases the HVR. This secondary increase persists after exposure to CSH and involves plasticity within the circuits in the central nervous system that control breathing. Currently these mechanisms of HVR plasticity are unknown and we hypothesized that they involve glutamatergic synapses in the nucleus tractus solitarius (NTS), where afferent endings from arterial chemoreceptors terminate. To test this, we treated rats held in normoxia (CON) or 10% O2 (CSH) for 7 days and measured ventilation in conscious, unrestrained animals before and after microinjecting glutamate receptor agonists and antagonists into the NTS. In normoxia, AMPA increased ventilation 25% and 50% in CON and CSH, respectively, while NMDA doubled ventilation in both groups (P < 0.05). Specific AMPA and NMDA receptor antagonists (NBQX and MK801, respectively) abolished these effects. MK801 significantly decreased the HVR in CON rats, and completely blocked the acute HVR in CSH rats but had no effect on ventilation in normoxia. NBQX decreased ventilation whenever it was increased relative to normoxic controls; i.e. acute hypoxia in CON and CSH, and normoxia in CSH. These results support our hypothesis that glutamate receptors in the NTS contribute to plasticity in the HVR with CSH. The mechanism underlying this synaptic plasticity is probably glutamate receptor modification, as in CSH rats the expression of phosphorylated NR1 and GluR1 proteins in the NTS increased 35% and 70%, respectively, relative to that in CON rats.