Activation of astrocytic PAR1 receptors in the rat nucleus of the solitary tract regulates breathing through modulation of presynaptic TRPV1

Abstract

Many of the cellular and molecular mechanisms underlying astrocytic modulation of synaptic function remain poorly understood. Recent studies show that G-protein coupled receptor-mediated astrocyte activation modulates synaptic transmission in the nucleus of the solitary tract (NTS), a brainstem nucleus that regulates crucial physiological processes including cardiorespiratory activity. By using calcium imaging and patch clamp recordings in acute brain slices of wild-type and TRPV1 rats, we show that activation of proteinase-activated receptor 1 (PAR1) in NTS astrocytes potentiates presynaptic glutamate release on NTS neurons. This potentiation is mediated by both a TRPV1-dependent and a TRPV1-independent mechanism. The TRPV1-dependent mechanism appears to require release of endovanilloid-like molecules from astrocytes, which leads to subsequent potentiation of presynaptic glutamate release via activation of presynaptic TRPV1 channels. Activation of NTS astrocytic PAR1 receptors elicits cFOS expression in neurons that project to respiratory premotor neurons and inhibits respiratory activity in control, but not in TRPV1 rats. Thus, activation of astrocytic PAR1 receptor in the NTS leads to a TRPV1-dependent excitation of NTS neurons causing a potent modulation of respiratory motor output.

Interaction between TRPV1-expressing neurons in the hypothalamus

“…On the other hand, we have to note that the subset of responding neurons in the presence of FC was smaller (25%) compared with the absence of astrocyte neutralizer (55%). Accordingly, astrocytes likely play a role in modulating TRPV1-expressing neurons; however, further detailed studies are required to delineate the exact contribution of astrocytes (Huda et al 2018).…”

“…4D) and also failed to cause an overall baseline shift (Ϫ29.80 Ϯ 3.31 pA vs. Ϫ30.48 Ϯ 3.35 pA; 1-way ANOVA, P ϭ 0.16, F ϭ 2.32). Since glial cells in the hypothalamus express TRPV1 (Huda et al 2018;Mannari et al 2013), we determined the contribution of astrocytes to the observed capsaicin effect. Astrocytes were neutralized with FC, and the effect of capsaicin on mEPSCs was determined.…”

Astrocytes in the nucleus of the solitary tract: Contributions to neural circuits controlling physiology

“…Activation of PAR1 on NTS astrocytes increased intracellular Ca 2+ in neighbouring neurons via direct activation of NMDARs and by increasing presynaptic glutamate release [37] . The presynaptic effects of PAR1 activation appear to be mediated by transient receptor potential cation channel subfamily V member 1 (TRPV1) since they were absent in the presence of TRPV1 antagonists (capsazepine or SB366791) or in TRPV1 knock out rats [117] . Given that PAR1 is activated by serine proteases, including thrombin, it has been proposed that this system may be responsible for the autonomic dysfunction observed in patients suffering bleeding head injuries [116] .…”

Thrombin action on astrocytes in the hindbrain of the rat disrupts glycemic and respiratory control

“…Surprisingly, blockade of NMDA or TRPV1 gliotransmission had no effect to inhibit thrombininduced increases in plasma glucose. This is in contrast to the thrombin-astrocyte-glutamate gliotransmission responsible for gastroparesis (31,74) and earlier reports concerning the involvement of TRPV1 channels in PAR suppression of respiratory control circuits (33). The involvement of purinergic gliotransmitter release in the thrombin induction of hyperglycemia is paralleled by our recent work showing that astrocytes activated by low-glucose challenge trigger counterregulatory responses through the release of purinergic agonists (62,64).…”