Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri.
Pennington Biomedical Research Center, Baton Rouge, Louisiana.
Am J Physiol Regul Integr Comp Physiol. 2020 Mar 1;318(3):R545-R564. doi: 10.1152/ajpregu.00319.2019. Epub 2020 Jan 22.
Astrocytic excitatory amino acid transporters (EAATs) are critical to restraining synaptic and neuronal activity in the nucleus tractus solitarii (nTS). Relief of nTS EAAT restraint generates two opposing effects, an increase in neuronal excitability that reduces blood pressure and breathing and an attenuation in afferent [tractus solitarius (TS)]-driven excitatory postsynaptic current (EPSC) amplitude. Although the former is due, in part, to activation of ionotropic glutamate receptors, there remains a substantial contribution from another unidentified glutamate receptor. In addition, the mechanism(s) by which EAAT inhibition reduced TS-EPSC amplitude is unknown. Metabotropic glutamate receptors (mGluRs) differentially modulate nTS excitability. Activation of group I mGluRs on nTS neuron somas leads to depolarization, whereas group II/III mGluRs on sensory afferents decrease TS-EPSC amplitude. Thus we hypothesize that EAATs control postsynaptic excitability and TS-EPSC amplitude via restraint of mGluR activation. To test this hypothesis, we used in vivo recording, brain slice electrophysiology, and imaging of glutamate release and TS-afferent Ca. Results show that EAAT blockade in the nTS with (3)-3-[[3-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]-l-aspartic acid (TFB-TBOA) induced group I mGluR-mediated depressor, bradycardic, and apneic responses that were accompanied by neuronal depolarization, elevated discharge, and increased spontaneous synaptic activity. Conversely, upon TS stimulation TFB-TBOA elevated extracellular glutamate to decrease presynaptic Ca and TS-EPSC amplitude via activation of group II/III mGluRs. Together, these data suggest an important role of EAATs in restraining mGluR activation and overall cardiorespiratory function.
星形细胞兴奋性氨基酸转运体（EAATs）对于抑制孤束核（nTS）中的突触和神经元活动至关重要。nTS EAAT 抑制的缓解会产生两种相反的效果，即神经元兴奋性增加，导致血压和呼吸降低，以及传入[孤束束（TS）]驱动的兴奋性突触后电流（EPSC）幅度减小。尽管前者部分归因于离子型谷氨酸受体的激活，但仍有相当一部分来自另一种未识别的谷氨酸受体。此外，EAAT 抑制降低 TS-EPSC 幅度的机制尚不清楚。代谢型谷氨酸受体（mGluRs）对 nTS 兴奋性有差异调节作用。nTS 神经元胞体上的 I 组 mGluR 激活导致去极化，而感觉传入上的 II/III 组 mGluR 则降低 TS-EPSC 幅度。因此，我们假设 EAAT 通过抑制 mGluR 激活来控制突触后兴奋性和 TS-EPSC 幅度。为了验证这一假设，我们使用了体内记录、脑片电生理学以及谷氨酸释放和 TS-传入 Ca 的成像。结果表明，nTS 中（3）-3-[[3-[[4-（三氟甲基）苯甲酰基]氨基]苯氧基]-l-天冬氨酸（TFB-TBOA）阻断 EAAT 会诱导 I 组 mGluR 介导的降压、心动过缓和呼吸暂停反应，同时伴随着神经元去极化、放电增加和自发突触活动增加。相反，在 TS 刺激下，TFB-TBOA 升高细胞外谷氨酸，通过激活 II/III 组 mGluR 降低突触前 Ca 和 TS-EPSC 幅度。总之，这些数据表明 EAAT 在抑制 mGluR 激活和整体心肺功能方面发挥着重要作用。
