Learning and memory in the brain are thought to be dependent on synaptic plasticity. In response to sensory input, synapses can be strengthened or weakened, known as long-term potentiation or long-term depression (LTD), respectively. Transient receptor potential vanilloid 1 (TRPV1) has been shown to mediate a novel form of presynaptic LTD in hippocampal interneurons. TRPV1 is currently being heavily studied in the PNS and being targeted by pharmaceuticals for its anti-nociceptive and anti-inflammatory properties. However, much less is known regarding TRPV1 function in the CNS, including the signal mechanism mediating hippocampal LTD despite its obvious importance. Here we performed whole-cell voltage clamp electrophysiology experiments from CA1 hippocampal interneurons to identify this signaling mechanism. Because calcineurin (CaN) is reported to be linked to multiple forms of synaptic plasticity, we hypothesized that TRPV1 activates presynaptic CaN, which is required for this presynaptic LTD. In order to distinguish between presynaptic and postsynaptic CaN activity we added the specific CaN inhibitors cyclosporin A (CsA) or FK-506 to the bath to block CaN activity ubiquitously in the slice, both presynaptically and postsynaptically, and to the internal solution to block CaN only in the postsynaptic neuron. CsA or FK-506 present in the internal solution, blocking only postsynaptic CaN, showed no effect on TRPV1-dependant LTD. Bath application of CsA or FK-506, inhibiting CaN in the presynaptic neuron as well, blocked LTD elicited by both a high frequency stimulation protocol (P < 0.05) and by direct TRPV1 activation with specific agonists resiniferotoxin and capsaicin (P < 0.05). This demonstrates that CsA and FK506 block both high frequency stimulation induced LTD and also TRPV1 specific depression. We are thus able to show that calcineurin is required for this form of presynaptic TRPV1 mediated LTD in the hippocampus. This finding is the first to demonstrate a TRPV1-induced signaling mechanism in CA1 hippocampus.



College and Department

Life Sciences; Physiology and Developmental Biology



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calcineurin, Long-term depression, TRPV1