Abstract
The brainstem nucleus tractus solitarii (nTS) processes and modulates the afferent arc of critical peripheral cardiorespiratory reflexes. Sensory afferents release glutamate to initiate the central component of these reflexes, and glutamate concentration is critically controlled by its removal via astrocytic neurotransmitter transporters. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the nTS providing tonic and phasic modulation of neuronal activity. GABA is removed from the extracellular space through GABA transporters (GATs), however, the role of GATs in nTS synaptic transmission and their influence on cardiorespiratory function is unknown. We hypothesized that GATs tonically restrain nTS inhibitory signaling and given the considerable nTS GABA-glutamate cross-talk, modify excitatory signaling and thus cardiorespiratory function. Reverse transcription real-time polymerase chain reaction (RT-PCR), immunoblot and immunohistochemistry showed expression of GAT-1 and GAT-3 mRNA and protein within the rat nTS, with GAT-3 greater than GAT-1, and GAT-3 colocalizing with astrocyte S100B. Recordings in rat nTS slices demonstrated GAT-3 block decreased spontaneous inhibitory postsynaptic current (IPSC) frequency and reduced IPSC amplitude evoked from electrical stimulation of the medial nTS. Block of GAT-3 also increased spontaneous excitatory postsynaptic current (EPSC) frequency yet did not alter sensory afferent-evoked EPSC amplitude. Block of GAT-3 in the nTS of anesthetized rats increased mean arterial pressure, heart rate, sympathetic nerve activity, and minute phrenic nerve activity. These results demonstrate inhibitory and excitatory neurotransmission in the nTS is significantly modulated by endogenous GAT-3 to influence basal cardiorespiratory function.
Highlights
The brainstem nucleus tractus solitarii is the first central site for integration and modulation of multiple cardiorespiratory sensory reflexes and is critical for autonomic homeostasis
real-time polymerase chain reaction (RT-PCR) confirmed expression of GABA transporters (GATs)-1 and GAT-3 mRNA, with relatively greater expression of GAT-3 compared to GAT-1 (Figure 1A, paired t-test, N = 6)
Immunohistochemistry provided the anatomical confirmation that GAT-1 and -3 are expressed in the nucleus tractus solitarii (nTS), and GAT-3 colabeled with S100B-labeled astrocytes and surrounded GAD67labeled Gamma-aminobutyric acid (GABA) terminals
Summary
The brainstem nucleus tractus solitarii (nTS) is the first central site for integration and modulation of multiple cardiorespiratory sensory reflexes and is critical for autonomic homeostasis. We have previously demonstrated astrocytes within the nTS tripartite synapse critically control glutamate signaling and cardiorespiratory baseline and reflex function (Matott et al, 2016, 2017; Martinez et al, 2020b) Such modulation occurs via the tonic modulation of glutamate in the extracellular space via astrocytic excitatory amino acid transporters (EAATs), which play important roles in synaptic transmission and its alterations in response to prolonged hypoxia (Martinez et al, 2020a; Matott et al, 2020). We hypothesized that GATs tonically restrain nTS GABA tone to balance inhibition and excitation thereby influencing baseline cardiorespiratory function. To test this hypothesis, we determined the expression and synaptic and physiological roles of GATs, primarily GAT-3 in the caudomedial nTS
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