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

• Published in: Journal of neurophysiology 2020-06, Vol.123 (6), p.2122-2135
• Main Authors: Martinez, Diana, Rogers, Richard C, Hasser, Eileen M, Hermann, Gerlinda E, Kline, David D
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes - physiology; Chemoreceptor Cells - physiology; Disease Models, Animal; Excitatory Postsynaptic Potentials - physiology; Glutamate Plasma Membrane Transport Proteins - antagonists & inhibitors; Glutamate Plasma Membrane Transport Proteins - metabolism; Glutamic Acid - metabolism; Hypoxia - metabolism; Hypoxia - physiopathology; Male; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; Sleep Apnea, Obstructive - metabolism; Sleep Apnea, Obstructive - physiopathology; Solitary Nucleus - metabolism; Solitary Nucleus - physiopathology
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.00766.2019

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 -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 to compare nTS properties of rats exposed to 10 days of normoxia (Norm; 21%O ) or CIH. Results show that EAAT blockade with (3 )-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 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. 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.