Calcineurin is required for TRPV1-induced long-term depression of hippocampal interneurons

Transient receptor potential vanilloid 1 (TRPV1) mediates a novel form of presynaptic long-term depression (LTD) in hippocampal interneurons. To date, while TRPV1 is currently being heavily studied in the PNS for its anti-nociceptive and anti-inflammatory properties, much less is known regarding TRPV1 signaling and function in the CNS, including the mechanism mediating hippocampal interneuron LTD. Here we performed whole-cell voltage clamp electrophysiology experiments on CA1 hippocampal interneurons from Sprague-Dawley male rats to identify this signaling mechanism. Because calcineurin is linked to multiple synaptic plasticity types, we investigated whether TRPV1 activates presynaptic calcineurin, which in turn induces LTD. To do so we employed calcineurin inhibitors cyclosporin A or FK-506. To determine the location of the calcineurin involved we either bath applied calcineurin antagonists, blocking calcineurin activity ubiquitously in the slice, presynaptically and postsynaptically, or applied antagonists to the internal solution to block calcineurin postsynaptically. Both calcineurin antagonists applied to the bath blocked TRPV1-dependent LTD, indicating calcineurin involvement in LTD. Because calcineurin antagonist applied to the internal solution did not block TRPV1-LTD, it suggests presynaptic calcineurin is required for LTD. Finally, because high frequency stimulus used to induce LTD could potentially activate receptors besides TRPV1, we confirmed that bath, but not intracellularly applied cyclosporin A, also blocked TRPV1 agonist-induced depression of CA1 interneurons. In conclusion, these data illustrate that presynaptic calcineurin activity is required for both TRPV1-induced LTD and TRPV1 agonist-induced depression. This finding is the first to demonstrate the TRPV1-induced signaling mechanism in CA1 hippocampus.