Primary Afferent Activation of Thermosensitive TRPV1 Triggers Asynchronous Glutamate Release at Central Neurons

Abstract

SUMMARY TRPV1 receptors feature prominently in nociception of spinal primary afferents but are also expressed in unmyelinated cranial visceral primary afferents linked to homeostatic regulation. Cranial visceral afferents enter the brain at the solitary tract nucleus (NTS) to control the heart, lungs and other vital organs. Here we identify a novel role for central TRPV1 in the activity-dependent facilitation of glutamatergic transmission from solitary tract (ST) afferents. Fast, synchronous ST-NTS transmission from capsaicin sensitive (TRPV1+) and insensitive (TRPV1−) afferents was similar. However, afferent activation triggered long lasting asynchronous glutamate release only from TRPV1+ synapses. Asynchronous release was proportional to synchronous EPSC amplitude, activity, and calcium entry. TRPV1 antagonists and low temperature blocked asynchronous release but not evoked EPSCs. At physiological afferent frequencies, asynchronous release strongly potentiated the duration of postsynaptic spiking. This activity dependent TPRV1-mediated facilitation is a novel form of synaptic plasticity that brings a unique central integrative feature to the CNS and autonomic regulation.

TRPV1 Channels Regulate Cortical Excitability in Humans

“…Notably, SNP variants of the TRPV1 channels failed to affect iTBS and cTBS responses in our study, although the induction of hippocampal LTP/LTD requires the activation of TRPV1 channels (Marsch et al, 2007;Gibson et al, 2008;Peters et al, 2010;Zhou et al, 2010). One possible explanation for this finding is that MEP changes secondary to TBS are already maximal in wild-type SNP rs222747 subjects and cannot be therefore further potentiated by enhancing the function of TRPV1 channels in the homozygous GG genotype.…”

“…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).…”

Calibration of Thresholds for Functional Engagement of Vagal A, B and C Fiber Groups In Vivo

“…Both A fiber and C fiber vagal afferent terminals impinging on secondary neurons in the nucleus of the solitary tract cause a synchronous excitatory synaptic event (and usually a postsynaptic action potential) in their respective second order neurons. But C fiber afferents then release further transmitter (glutamate), asynchronously giving rise to further action potentials over the next second or two, rather than the single spike evoked by A fiber afferents [24]. The TRPV1 receptor on C fiber afferents underlies this further release of transmitter [24].…”

“…But C fiber afferents then release further transmitter (glutamate), asynchronously giving rise to further action potentials over the next second or two, rather than the single spike evoked by A fiber afferents [24]. The TRPV1 receptor on C fiber afferents underlies this further release of transmitter [24].…”

Nicotine enhances inhibition of mouse vagal motor neurons by modulating excitability of premotor GABAergic neurons in the nucleus tractus solitarii

“…For example, cytisine could affect a pool of vesicles with agonist sensitivities different from the primary vesicle pool released after stimulation of primary afferents (Fawley et al 2014). The drug could also affect different mechanisms of release at vagal afferent terminals versus terminals of other neurons, as can occur with TRPV1 activation (Peters et al 2010). A similar increase in PPr, in combination with increased mEPSC frequency, has also been reported after positive modulation of AMPA receptors in the calyx of Held (Bellingham and Walmsley 1999), which was attributed to a Ca 2ϩ -independent mechanism of enhanced glutamate release.…”