TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus

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Abstract
The authors report that the cation channel TRPV1 suppresses excitatory synaptic transmission in dentate gyrus via a Ca2+-calcineurin and clathrin-dependent internalization of AMPA receptors. Activation of TRPV-1 triggers a form of LTD that is mediated by anandamide, but is independent of type 1 endocannabinoid receptors. The transient receptor potential TRPV1 is a nonselective cation channel that mediates pain sensations and is commonly activated by a wide variety of exogenous and endogenous, physical and chemical stimuli. Although TRPV1 receptors are mainly found in nociceptive neurons of the peripheral nervous system, these receptors have also been found in the brain, where their role is far less understood. Activation of TRPV1 reportedly regulates neurotransmitter release at several central synapses. However, we found that TRPV1 suppressed excitatory transmission in rat and mouse dentate gyrus by regulating postsynaptic function in an input-specific manner. This suppression was a result of Ca2+-calcineurin and clathrin-dependent internalization of AMPA receptors. Moreover, synaptic activation of TRPV1 triggered a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamide in a type 1 cannabinoid receptor–independent manner. Thus, our findings reveal a previously unknown form of endocannabinoid- and TRPV1-mediated regulation of synaptic strength at central synapses.