Loss of excitatory amino acid transporter restraint following chronic intermittent hypoxia contributes to synaptic alterations in nucleus tractus solitarii.

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  • Additional Information
    • Source:
      Publisher: American Physiological Society Country of Publication: United States NLM ID: 0375404 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1598 (Electronic) Linking ISSN: 00223077 NLM ISO Abbreviation: J Neurophysiol Subsets: MEDLINE
    • Publication Information:
      Publication: Bethesda Md : American Physiological Society
      Original Publication: Washington [etc.]
    • Subject Terms:
      Hypoxia*/metabolism ; Hypoxia*/physiopathology ; Sleep Apnea, Obstructive*/metabolism ; Sleep Apnea, Obstructive*/physiopathology ; Solitary Nucleus*/metabolism ; Solitary Nucleus*/physiopathology; Astrocytes/*physiology ; Chemoreceptor Cells/*physiology ; Excitatory Postsynaptic Potentials/*physiology ; Glutamate Plasma Membrane Transport Proteins/*metabolism ; Glutamic Acid/*metabolism ; Signal Transduction/*physiology; Animals ; Disease Models, Animal ; Glutamate Plasma Membrane Transport Proteins/antagonists & inhibitors ; Male ; Rats ; Rats, Sprague-Dawley
    • Abstract:
      Peripheral viscerosensory afferent signals are transmitted to the nucleus tractus solitarii (nTS) via release of glutamate. Following release, glutamate is removed from the extrasynaptic and synaptic cleft via excitatory amino acid transporters (EAATs), thus limiting glutamate receptor activation or over activation, and maintaining its working range. We have shown that EAAT block with the antagonist threo -β-benzyloxyaspartic acid (TBOA) depolarized nTS neurons and increased spontaneous excitatory postsynaptic current (sEPSC) frequency yet reduced the amplitude of afferent (TS)-evoked EPSCs (TS-EPSCs). Interestingly, chronic intermittent hypoxia (CIH), a model of obstructive sleep apnea (OSA), produces similar synaptic responses as EAAT block. We hypothesized EAAT expression or function are downregulated after CIH, and this reduction in glutamate removal contributes to the observed neurophysiological responses. To test this hypothesis, we used brain slice electrophysiology and imaging of glutamate release and TS-afferent Ca 2+ to compare nTS properties of rats exposed to 10 days of normoxia (Norm; 21%O 2 ) or CIH. Results show that EAAT blockade with (3 S )-3-[[3-[[4-(trifluoromethyl)benzoyl]-amino]phenyl]methoxy]-l-aspartic acid (TFB-TBOA) in Norm caused neuronal depolarization, generation of an inward current, and increased spontaneous synaptic activity. The latter augmentation was eliminated by inclusion of tetrodotoxin in the perfusate. TS stimulation during TFB-TBOA also elevated extracellular glutamate and decreased presynaptic Ca 2+ and TS-EPSC amplitude. In CIH, the effects of EAAT block are eliminated or attenuated. CIH reduced EAAT expression in nTS, which may contribute to the attenuated function seen in this condition. Therefore, CIH reduces EAAT influence on synaptic and neuronal activity, which may lead to the physiological consequences seen in OSA and CIH. NEW & NOTEWORTHY Removal of excitatory amino acid transporter (EAAT) restraint increases spontaneous synaptic activity yet decreases afferent [tractus solitarius (TS)]-driven excitatory postsynaptic current (EPSC) amplitude. In the chronic intermittent hypoxia model of obstructive sleep apnea, this restraint is lost due to reduction in EAAT expression and function. Thus EAATs are important in controlling elevated glutamatergic signaling, and loss of such control results in maladaptive synaptic signaling.
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    • Grant Information:
      R01 DK108765 United States DK NIDDK NIH HHS; R01 NS060664 United States NS NINDS NIH HHS; DK108765 International HHS | National Institutes of Health (NIH); R01 HL128454 United States HL NHLBI NIH HHS; HL128454 International HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)
    • Contributed Indexing:
      Keywords: astrocytes; chemoreflex; glutamate signaling
    • Accession Number:
      0 (Glutamate Plasma Membrane Transport Proteins)
      3KX376GY7L (Glutamic Acid)
    • Publication Date:
      Date Created: 20200430 Date Completed: 20210719 Latest Revision: 20230115
    • Publication Date:
      20230115
    • Accession Number:
      PMC7311725
    • Accession Number:
      10.1152/jn.00766.2019
    • Accession Number:
      32347148