Ionotropic and Metabotropic Glutamate Receptors Contribute to Cardiorespiratory Responses to Inhibition of Astrocytic Excitatory Amino Acid Transporters

Abstract

The nucleus tractus solitarii (nTS) is the initial site of termination of cardiorespiratory afferents, which transmit signals through release of glutamate (Glu). Afferent information is integrated extensively in the nTS, thus shaping its output and cardiorespiratory responses. We have shown that inhibition of astrocytic excitatory amino acid transporter 2 (EAAT2) in the nTS increased ambient [Glu] and altered basal and reflex cardiorespiratory function. These effects were partially blocked by ionotropic glutamate receptor (iGluR) antagonism. We hypothesized that the responses remaining after iGluR blockade were due to activation of metabotropic (m)GluRs. To test this, Inactin‐anesthetized rats were instrumented to record mean arterial pressure (MAP), heart rate (HR), splanchnic sympathetic and phrenic nerve activity (SSNA; PhNA), and for microinjections into the nTS. The general EAAT inhibitor TFB‐TBOA (10 μM, 90 nl) was microinjected unilaterally into the nTS. GluR antagonists or vehicle (aCSF) were then microinjected, followed by two additional injections of TBOA. Unilateral nTS microinjection of TBOA decreased MAP, HR, PhNA and SSNA, consistent with effects of increased [Glu] in the nTS. Following aCSF, additional injections of TBOA produced augmented as well as prolonged cardiorespiratory responses. Prior blockade of iGluRs with a cocktail (90 nl) of NBQX (2 mM) and AP5 (10 mM) reduced the response to EAAT inhibition. However, it did not prevent the augmented effects of repetitive TBOA, indicating a role for other receptors. The effects of combined blockade of iGluRs and Group II/III mGluRs (MSOP, 100 mM + eGlu, 10 mM; 90 nl total) were similar to those of iGluR antagonism alone. In contrast, combined blockade of iGluRs and Group I mGluRs (LY367385, 10 mM; 90 nl total) blunted the cardiorespiratory effects of nTS EAAT inhibition, and markedly attenuated enhanced responses to subsequent injection of TBOA. These data are consistent with the concept that nTS inhibition of astrocytic EAATs increases [Glu], producing cardiorespiratory responses similar to excitation of nTS neurons involved in baroreflex function. These effects of EAAT inhibition are mediated primarily by iGluRs and Group I mGluRs. It is possible that Group II/III mGluRs also contribute via other mechanisms.Support or Funding InformationSupported by HL132836 and HL128454This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.