Transient Receptor Potential Vanilloid 1 Function at Central Synapses in Health and Disease

Abstract

The transient receptor potential vanilloid 1 (TRPV1), a ligand-gated nonselective cation channel, is well known for mediating heat and pain sensation in the periphery. Increasing evidence suggests that TRPV1 is also expressed at various central synapses, where it plays a role in different types of activity-dependent synaptic changes. Although its precise localizations remain a matter of debate, TRPV1 has been shown to modulate both neurotransmitter release at presynaptic terminals and synaptic efficacy in postsynaptic compartments. In addition to being required in these forms of synaptic plasticity, TRPV1 can also modify the inducibility of other types of plasticity. Here, we highlight current evidence of the potential roles for TRPV1 in regulating synaptic function in various brain regions, with an emphasis on principal mechanisms underlying TRPV1-mediated synaptic plasticity and metaplasticity. Finally, we discuss the putative contributions of TRPV1 in diverse brain disorders in order to expedite the development of next-generation therapeutic treatments.

Keywords: brain; endocannabinoids; neurotransmision; synaptic function; vanilloid receptor.

FIGURE 1

Mechanisms described for TRPV1-mediated plasticity at central synapses. Glutamate release during synaptic stimulation activates Gq-coupled mGluRs, leading to the activation of phospholipase C (PLC) and downstream calcium-regulated enzymes, which likely triggers the biosynthesis of lipids including 12-HPETE (presynaptic TRPV1-LTD, left) or AEA (postsynaptic TRPV1-LTD, middle), two endocannabinoid/endovanilloid known to activate TRPV1 receptors. At presynaptic terminals, activation of TRPV1 on plasma membrane or intracellular compartments (IC) leads to a calcium (Ca²⁺)-dependent long-term depression of synaptic vesicle release, whereas when located at postsynaptic compartments, TRPV1 activation promotes a long-lasting, clathrin- and dynamin (Dyn)-dependent endocytosis of AMPA receptors. Notably, stimulation of calcium-sensitive phosphatase calcineurin (CaN) resulting from TRPV1 activation is likely to be a common mechanism to promote both pre and postsynaptic long-term changes of synaptic efficacy. TRPV1 channels are also expressed in glial cells (right), where its activation can modulate synaptic efficacy presumably through the production and release of inflammatory mediators through microglia-derived extracellular vesicles (EVs) or by Ca²⁺-dependent release of gliotransmitters from astrocytes.

FIGURE 2

Potential mechanisms for TRPV1-dependent metaplasticity at central synapses. Top, Calcium influx through TRPV1 channels triggers a form of postsynaptic LTD that require endocytosis of AMPARs, which may counterbalance the level of N-methyl-D-aspartate receptor (NMDAR) dependent LTP (1). In contrast, blockade or genetic deletion of TRPV1 channels recovers NMDAR-mediated LTP that may be due to the absence of TRPV1-LTD (2). Bottom, NMDAR-dependent LTP can be reduced by activation of GABA_ARs (1). Activation of TRPV1 channels could triggers a calcineurin (CaN) and dynamin (Dyn)-dependent endocytosis of GABA_ARs that remove the inhibitory suppression of the LTP (2). Exogenous activation of nicotinic acetylcholine receptors (nAChR) may oppose the influence of GABAergic inhibition and rescue LTP in the absence of TRPV1 likely by increasing calcium levels (3).