Sustained Hypoxia Alters nTS Glutamatergic Signaling and Expression and Function of Excitatory Amino Acid Transporters

Neuroscience. 2020 Mar 15;430:131-140. doi: 10.1016/j.neuroscience.2020.01.034. Epub 2020 Feb 4.


Glutamate is the major excitatory neurotransmitter in the nucleus tractus solitarii (nTS) and mediates chemoreflex function during periods of low oxygen (i.e. hypoxia). We have previously shown that nTS excitatory amino acid transporters (EAATs), specifically EAAT-2, located on glia modulate neuronal activity, cardiorespiratory and chemoreflex function under normal conditions via its tonic uptake of extracellular glutamate. Chronic sustained hypoxia (SH) elevates nTS synaptic transmission and chemoreflex function. The goal of this study was to determine the extent to which glial EAAT-2 contributes to SH-induced nTS synaptic alterations. To do so, male Sprague-Dawley rats (4-7 weeks) were exposed to either 1, 3, or 7 days of SH (10% O2, 24 h/day) and compared to normoxic controls (21% O2, 24 h/day, i.e., 0 days SH). After which, the nTS was harvested for patch clamp electrophysiology, quantitative real-time PCR, immunohistochemistry and immunoblots. SH induced time- and parameter-dependent increases in excitatory postsynaptic currents (EPSCs). TS-evoked EPSC amplitude increased after 1D SH which returned at 3D and 7D SH. Spontaneous EPSC frequency increased only after 3D SH, which returned to normoxic levels at 7D SH. EPSC enhancement occurred primarily by presynaptic mechanisms. Inhibition of EAAT-2 with dihydrokainate (DHK, 300 µM) did not alter EPSCs following 1D SH but induced depolarizing inward currents (Ihold). After 3D SH, DHK decreased TS-EPSC amplitude yet its resulting Ihold was eliminated. EAAT-2 mRNA and protein increased after 3D and 7D SH, respectively. These data suggest that SH alters the expression and function of EAAT-2 which may have a neuroprotective effect.

Keywords: astroglia; autonomic nervous system; chemoreflex; glutamate; respiration; synaptic transmission.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Transport Systems
  • Animals
  • Glutamic Acid*
  • Hypoxia
  • Male
  • Neurotransmitter Agents
  • Rats
  • Rats, Sprague-Dawley
  • Solitary Nucleus*
  • Synaptic Transmission


  • Amino Acid Transport Systems
  • Neurotransmitter Agents
  • Glutamic Acid