Thermally Active TRPV1 Tonically Drives Central Spontaneous Glutamate Release

Abstract

Central synapses spontaneously release neurotransmitter at low rates. In the brainstem, cranial visceral afferent terminals in caudal solitary tract nucleus (NTS) display pronounced, activity-dependent, asynchronous release of glutamate and this extra release depends on TRPV1 receptors (TRPV1ϩ). Asynchronous release is absent for afferents lacking TRPV1 (TRPV1Ϫ) and resting EPSC frequency was greater in TRPV1ϩ. Here, we studied this basal activity difference by assessing thermal sensitivity of spontaneous and miniature synaptic events in TRPV1ϩ and TRPV1Ϫ second-order NTS neurons. The spontaneous EPSC rate decreased when temperature was decreased, increased steeply between 30 and 42°C only in TRPV1ϩ neurons, and was calcium-dependent. TRPV1-specific antagonist SB366791, but not TTX, strongly attenuated thermal responses. Temperature changes failed to alter EPSC frequency in TRPV1Ϫ neurons. EPSC amplitudes and decay kinetics changed little with temperature. IPSCs in these second-order NTS neurons were unaltered by temperature. Such results suggest that activated, presynaptic TRPV1ϩ receptors trigger continuous resting release of glutamate vesicles at physiological temperatures only in capsaicin-responsive terminals. In mechanically isolated individual neurons harvested from medial NTS, increases in temperature increased the rate of glutamate release only in TRPV1ϩ neurons, whereas IPSC rates were unaffected. Cadmium failed to block thermal increases in glutamate release, suggesting that calcium entry through TRPV1 channels may trigger glutamate release independently of voltage-activated calcium channels. Together, our findings indicate a new form of afferent signaling in which TRPV1 channels within central terminals of peripheral afferents tonically generate glutamate release in NTS at 37°C in the absence of afferent action potentials.

Physiological temperatures drive glutamate release onto trigeminal superficial dorsal horn neurons

“…5D). This proximity suggested that CAP sensitivity may correlate with thermal sensitivity as previously observed in NTS (Shoudai et al 2010). Although the majority of Vc neurons (67%, n ϭ 36 of 54; Fig.…”

“…However, at central synapses measured in slices, neurotransmitter release occurs spontaneously, and such events are commonly viewed as arising from infrequent and stochastic release from the same pools of vesicles as action potential-evoked release (Ermolyuk et al 2013;Katz 1971). In contrast to peripheral activation characteristics, the rates of spontaneous vesicle release are often much higher from primary afferent terminals (Grudt and Williams 1994;Shoudai et al 2010;Uta et al 2010). Indeed, primary afferents that contact second-order neurons in the solitary tract nucleus (NTS) often express the transient receptor potential (TRP) vanilloid type 1 channel (TRPV1) and have substantially higher spontaneous glutamate release rates than neurons with afferents lacking TRPV1 .…”

“…Indeed, primary afferents that contact second-order neurons in the solitary tract nucleus (NTS) often express the transient receptor potential (TRP) vanilloid type 1 channel (TRPV1) and have substantially higher spontaneous glutamate release rates than neurons with afferents lacking TRPV1 . The spontaneous excitatory postsynaptic current (sEPSC) rates in NTS strongly depend on the ambient temperature for the TRPV1-expressing afferents (Shoudai et al 2010) and are independent of voltageactivated calcium channels yet strongly modulated by G protein-coupled receptors (GPCRs; Fawley et al 2011). The high sensitivity near 37°C contrasts to the relatively weak thermal sensitivity at physiological temperatures of neural excitability and conduction more generally (Hardingham and Larkman 1998;Klyachko and Stevens 2006;Pyott and Rosenmund 2002).…”

TRPV1 Channels Regulate Cortical Excitability in Humans

“…Studies in animals show that these channels are involved in the regulation of synaptic transmission in peripheral (Caterina et al, 1997;Sikand and Premkumar, 2007) and central (Gibson et al, 2008;Peters et al, 2010;Shoudai et al, 2010) structures, by enhancing glutamate release from nerve endings. Accordingly, physiological studies have shown that stimulation of TRPV1 channels with capsaicin or anandamide enhances the frequency of glutamate-mediated spontaneous and miniature EPSCs, whereas GABAergic synaptic transmission is unaffected (Yang et al, 1998;Marinelli et al, 2002Marinelli et al, , 2003Li et al, 2004;Derbenev et al, 2006;Starowicz et al, 2007;Xing and Li, 2007;Musella et al, 2009).…”

“…Accordingly, physiological studies have shown that stimulation of TRPV1 channels with capsaicin or anandamide enhances the frequency of glutamate-mediated spontaneous and miniature EPSCs, whereas GABAergic synaptic transmission is unaffected (Yang et al, 1998;Marinelli et al, 2002Marinelli et al, , 2003Li et al, 2004;Derbenev et al, 2006;Starowicz et al, 2007;Xing and Li, 2007;Musella et al, 2009). Recent studies also show that the regulation of spontaneous glutamate release by TRPV1 receptors is activity dependent Shoudai et al, 2010), because afferent activation triggers long-lasting asynchronous glutamate release only from synapses expressing the TRPV1 receptor, strongly potentiating the duration of postsynaptic spiking . TRPV1 has also been involved in the regulation of synaptic plasticity and in particular in hippocampal long-term potentiation (LTP) (Marsch et al, 2007) and depression (LTD) (Gibson et al, 2008) and also in hippocampus-dependent learning in mice (Marsch et al, 2007).…”