Temperature Differentially Facilitates Spontaneous but Not Evoked Glutamate Release from Cranial Visceral Primary Afferents

Abstract

Temperature is fundamentally important to all biological functions including synaptic glutamate release. Vagal afferents from the solitary tract (ST) synapse on second order neurons in the nucleus of the solitary tract, and glutamate release at this first central synapse controls autonomic reflex function. Expression of the temperature-sensitive Transient Receptor Potential Vanilloid Type 1 receptor separates ST afferents into C-fibers (TRPV1+) and A-fibers (TRPV1-). Action potential-evoked glutamate release is similar between C- and A-fiber afferents, but TRPV1 expression facilitates a second form of synaptic glutamate release in C-fibers by promoting substantially more spontaneous glutamate release. The influence of temperature on different forms of glutamate release is not well understood. Here we tested how temperature impacts the generation of evoked and spontaneous release of glutamate and its relation to TRPV1 expression. In horizontal brainstem slices of rats, activation of ST primary afferents generated synchronous evoked glutamate release (ST-eEPSCs) at constant latency whose amplitude reflects the probability of evoked glutamate release. The frequency of spontaneous EPSCs in these same neurons measured the probability of spontaneous glutamate release. We measured both forms of glutamate from each neuron during ramp changes in bath temperature of 4–5°C. Spontaneous glutamate release from TRPV1+ closely tracked with these thermal changes indicating changes in the probability of spontaneous glutamate release. In the same neurons, temperature changed axon conduction registered as latency shifts but ST-eEPSC amplitudes were constant and independent of TRPV1 expression. These data indicate that TRPV1-operated glutamate release is independent of action potential-evoked glutamate release in the same neurons. Together, these support the hypothesis that evoked and spontaneous glutamate release originate from two pools of vesicles that are independently modulated and are distinct processes.

Central control of body temperature

“…Providing an additional layer of complexity in the CNS regulation of T core is the presence of the thermally responsive TRPV1 channel in the membranes of a variety of classically non-thermal, unmyelinated afferents 85 – 88 that may have access to central thermoregulatory circuits, including via NTS neurons that can inhibit thermogenesis 59 . The finding that the TRPV1 responsiveness to local brain temperature alters spontaneous glutamate release from the terminals of unmyelinated vagal afferents 88 , 89 provides a potential substrate for T core to modulate the activity of second-order sensory neurons in NTS that modulate thermoeffector activation. Importantly, TRPV1 channels are also activated by non-thermal factors, including low (or high) pH, inorganic cations, or endovanilloids, thereby providing a basis for such factors to influence thermoeffector activation and thus T core .…”

Vanilloids selectively sensitize thermal glutamate release from TRPV1 expressing solitary tract afferents

“…2C and D). The arrival time (evoked latency) shortened with warming suggesting a thermal acceleration of conduction velocity – a consistent action on ST-EPSCs for TRPV1+ and TRPV1- afferents (Fawley et al , 2015). Thus, normal brain temperatures foster enhanced glutamate release rates from the TRPV1-operated pool without affecting the evoked pool release probability providing additional evidence for two separate vesicle pools at primary afferent terminals within the NTS.…”

“…In second order NTS neurons, small increments in bath temperature near 36°C rapidly and reversibly alter the sEPSC rate only in those neurons receiving TRPV1+ afferents (Shoudai et al , 2010; Fawley et al , 2015). Increasing the temperature by 4°C nearly doubled the frequency of sEPSCs (Fig.…”

“…TRPV1 located at unmyelinated, C-fiber ST afferent synaptic terminals acts as a unique calcium source to trigger glutamate vesicle release registered as spontaneous EPSCs (sEPSCs). Surprisingly, physiological temperatures vigorously activate TRPV1 to trigger spontaneous glutamate release only from TRPV1-expressing ST afferents, whereas cooling steeply suppresses spontaneous but not evoked synaptic responses (Peters et al , 2010; Shoudai et al , 2010; Fawley et al , 2015). This ongoing drive of TRPV1 at 37°C contrasts with the canonical noxious heat thresholds of other primary sensory afferents.…”

Thermo-dependence of noxious mechanical heterotopic stimulation-dependent modulation of the spinal dorsal horn response to somatosensory stimulation

“…Clinical range changes in temperature of the central nervous system affect membrane and neuronal properties [1,2]. Furthermore, thermal stress increases expression of heat-sensitive molecules and induces activation of several neuronal activity modulating factors even for a physiological temperature range [3].…”