Channeling satiation: A primer on the role of TRP channels in the control of glutamate release from vagal afferent neurons☆
Introduction
Primary vagal afferent neurons provide a direct neural pathway through which the status of peripheral organ systems (including the heart, lungs, and gastrointestinal tract) and satiety signals are relayed to the brain [1], [2], [3]. Vagal afferent neurons convey a broad range of stimuli which vary by information types, time-frames, and relative physiological urgencies. As a result, information transfer must be at once reliable and precise while maintaining plasticity to match autonomic function to the physiological state. To control information transfer, vagal afferents release the fast excitatory neurotransmitter glutamate via three distinct pathways: synchronous, asynchronous, and spontaneous (Fig. 1) [4]. The interplay between these multiple complementary vesicle release pathways allows for robust and precise information transfer which is also adaptable and plastic to changing physiological states.
Vagal afferent neurons are broadly divided into myelinated A-fibers, lightly myelinated Aδ-fibers, and unmyelinated C-fibers based off conduction velocity and histological analysis. C-fibers compose the majority of neurons in the vagus and robustly express the transient receptor potential vanilloid type 1 (TRPV1) ion channel thus conveying their sensitivity to capsaicin lesion [5]. Centrally vagal afferents converge with the facial (VII) and glossopharyngeal (IX) nerves to form the solitary tract (ST) bundle and innervate second-order NTS neurons [2]. Afferent innervation onto second-order NTS neurons is limited relative to central synapses; with as few as 1–5 discrete primary afferent inputs converging [6]. Further, convergent inputs are completely segregated based on their expression of TRPV1 or not [7]. This organizational schema allowed for the observation that the presence of TRPV1 in the central terminals predicts facilitated forms of quantal glutamate release; including higher frequencies of spontaneous and asynchronous quantal release compared to afferents lacking TRPV1 [4]. This activity-dependent asynchronous glutamate release prolongs the period of action potential driven release (from milliseconds to seconds) and extends the postsynaptic excitatory period despite frequency dependent depression (FDD) of synchronous glutamate release [4]. Furthermore, TRPV1, and likely other thermosensitive TRP channels, provide temperature sensitive calcium conductances which largely determine the rate of spontaneous vesicle fusion [8], [9]. We speculate that these additional vesicle release pathways contribute to the relative strength of C-fibers in activating autonomic reflex pathways, including those that control food intake and energy balance.
Here, we discuss the plasticity of vagal afferent signaling within the context of food intake and energy balance. We will discuss the different forms of glutamate release which define the adaptive nature of vagal afferent signaling and summarize evidence that thermosensitive TRP channels guide glutamate release pathways. Consideration of peripheral and central peptides and their effects on satiation through these glutamate release pathways will be given. In short, complementary vesicle release pathways, segregated innervation of vagal afferents, and presence of highly adaptable temperature sensitive TRP ion channels allow vagal afferent signaling to be predictive and reactive in order to efficiently maintain energy homeostasis. By elucidating the cellular mechanisms that enable the adaptive nature of vagal afferent, we hope to gain a better understanding of vagal afferent control of food intake and energy balance.
Section snippets
Spontaneous vesicle fusion and release
Spontaneous vesicle fusion is a stochastic but regulated process of neurotransmitter release which occurs independently of action-potential depolarization of the terminal (Fig. 1B, top panel) [10]. Individual vesicles fuse and are released probabilistically over time from pre-synaptic active zones. The average peak current amplitude generated by the glutamate released from single vesicles acting at the postsynaptic receptors represents the fundamental unit or quantum (q) of neurotransmission.
Vagal afferent ‘TRP’ channel expression
In this review, we present evidence to suggest that the presence of thermosensitive TRP channels in vagal afferents contributes to the neurocircuitry of feeding by maintaining adaptable synaptic transmission at the ST–NTS synapse. TRPV1 is expressed at the terminals of vagal afferent terminals specifically in C-type fibers and provides a unique form of asynchronous vesicular release as well as temperature sensitive spontaneous vesicular release [4], [9], [25]. Recent findings that involve
Synaptic plasticity and satiety signaling
Vagal afferents to NTS glutamatergic synaptic transmission maintains homeostasis of many physiological processes, including those that control food intake and energy balance. To maintain energy homeostasis, the neuronal circuits that convey peripheral information are matched with hormonal, nutrient, and neuronal signals of the organism. This neurocircuitry is robust and precise in its ability to transmit signals, yet the fidelity of these signals must change from moment to moment in order to
Conclusions and future directions
To maintain homeostasis of energy stores, vagal afferents carry satiety information to the central nervous system. To do so efficiently, it undergoes continuous change. Vagal afferent to NTS neurotransmission is at once robust and reliable while maintaining the ability to adapt to changing internal environments and physiological states. This balance of traits is a result of the segregation of primary afferent innervation, presence of temperatures sensitive TRP channels, and multiple forms of
Acknowledgments
This manuscript is based on work presented during the 2013 Annual Meeting of the Society for the Study of Ingestive Behavior, July 30–August 3, 2013.
References (51)
The vagus nerve, food intake and obesity
Regul Pept
(2008)- et al.
Primary afferent activation of thermosensitive TRPV1 triggers asynchronous glutamate release at central neurons
Neuron
(2010) - et al.
Unveiling synaptic plasticity: a new graphical and analytical approach
Trends Neurosci
(2000) - et al.
Dynamic expression of the TRPM subgroup of ion channels in developing mouse sensory neurons
Gene Expr Patterns
(2010) - et al.
TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation
Cell
(2010) - et al.
Heteromeric heat-sensitive transient receptor potential channels exhibit distinct temperature and chemical response
J Biol Chem
(2012) - et al.
TRPM3 Is a nociceptor channel involved in the detection of noxious heat
Neuron
(2011) - et al.
Hypothalamic control of energy balance: insights into the role of synaptic plasticity
Trends Neurosci
(2013) - et al.
Calcium channels and short-term synaptic plasticity
J Biol Chem
(2013) Central autonomic pathways
The central autonomic nervous system: conscious visceral perception and autonomic pattern generation
Annu Rev Neurosci
Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons
Pharmacol Rev
Convergence of cranial visceral afferents within the solitary tract nucleus
J Neurosci
TRPV1 marks synaptic segregation of multiple convergent afferents at the rat medial solitary tract nucleus
PLoS One
Isolation of TRPV1 independent mechanisms of spontaneous and asynchronous glutamate release at primary afferent to NTS synapses
Front Auton Neurosci
Thermally active TRPV1 tonically drives central spontaneous glutamate release
J Neurosci
Spontaneous neurotransmission: an independent pathway for neuronal signaling?
Physiology (Bethesda)
Seeking a function for spontaneous neurotransmission
Nat Neurosci
TRPV1-dependent regulation of synaptic activity in the mouse dorsal motor nucleus of the vagus nerve
Front. Auton. Neurosci.
The involvement of the sympathetic nervous system in meal-induced thermogenesis in mice
Int J Obes
Temperature as a universal resetting cue for mammalian circadian oscillators
Science
Molecular mechanisms for synchronous, asynchronous, and spontaneous neurotransmitter release
Annu Rev Physiol
Heterogeneous functional expression of calcium channels at sensory and synaptic regions in nodose neurons
J Neurophysiol
Cranial visceral afferent pathways through the nucleus of the solitary tract to caudal ventrolateral medulla or paraventricular hypothalamus: target-specific synaptic reliability and convergence patterns
J Neurosci
Vasopressin inhibits glutamate release via two distinct modes in the brainstem
J Neurosci
Cited by (13)
Dopamine controls neuronal spontaneous calcium oscillations via astrocytic signal
2021, Cell CalciumCitation Excerpt :Thus, effect of dopamine on neurons can be mediated by the activation of chloride currents and the corresponding suppression of the activity of the neural network. Spontaneous synchronous calcium oscillations in neurons can be induced by release of various types of neurotransmitters [36,37] but predominantly glutamate. Ability of dopamine to suppress glutamate-induced calcium signal and current in NMDA receptors was shown in details [16,17,34].
Principles of synaptic encoding of brainstem circadian rhythms
2024, Experimental PhysiologyRegulation of Presynaptic Calcium Channels
2023, Advances in NeurobiologyTRPM3 in Brain (Patho)Physiology
2021, Frontiers in Cell and Developmental BiologyTRPM3 expression and control of glutamate release from primary vagal afferent neurons
2021, Journal of Neurophysiology