TRPV1 (transient receptor potential vanilloid subfamily member 1) receptors have classically been defined as ligand-gated, non-selective cation channels that act as heat-, proton- and ligand-activated integrators of nociceptive stimuli in sensory neurons, and there has been great interest in TRPV1 as a novel therapeutic target for pain relief. TRPV1 receptors have also been identified in the brain, but their physiological role is poorly understood. Here we report for the first time that TRPV1 channel activation is necessary and sufficient to trigger long-term synaptic depression (LTD). Excitatory synapses onto hippocampal interneurons were depressed either by capsaicin, a potent TRPV1 activator, or by 12-(S)-HPETE, an endogenous eicosanoid released during synaptic stimulation, while neither compound affected excitatory synapses onto CA1 pyramidal cells. TRPV1 receptor antagonists also prevented the induction of interneuron LTD. Furthermore, in brain slices from transgenic mice lacking TRPV1 receptors, LTD was absent and neither capsaicin nor 12-(S)-HPETE elicited synaptic depression. Our results suggest that TRPV1 channel activation represents a novel mechanism capable of selectively modifying synapses onto hippocampal interneurons. Like other forms of synaptic plasticity, TRPV1-mediated LTD may have a role in long-term changes in the physiological and pathological behavior of neural circuits during learning and epileptic activity.