Capsaicin is the main pungent ingredient in hot chili peppers, which is consumed by nearly one-fourth of the world’s population on a daily basis. The capsaicin receptor is initially identified in sensory neurons and terms as TRPV1 for transient receptor potential vanilloid type-1 since it belongs to a large family of TRP ion channel. Capsaicin and TRPV1 have been extensively investigated in the pain perception, but their functions in the brain remains unclear. Accumulated evidences show that TRPV1 is expressed throughout the whole brain. In hippocampus, TRPV1 is expressed in many neurons throughout the dentate gyrus and CA3-CA1 subfield. At the subcellular level, TRPV1 can be detected predominantly on postsynaptic dendritic spines and cell soma. Recently, several endogenous ligands of TRPV1 have been characterized, which include anandamide (AEA), N-arachidonoyl-dopamine, and products of lipoxygenases. Capsaicin acting at TRPV1 has been demonstrated to modulate neuronal excitability and transmitter release in various brain regions, including hippocampus. Hippocampal bi-directional synaptic plasticity, long-term potentiation (LTP) and depression (LTD), is believed to underlie certain types of learning and memory. It is well known that the different level of NMDAR activation and the subsequently distinct Ca2+ signals determine the threshold of LTP/LTD. Therefore, changes in Ca2+ signaling are one of the most direct ways to alter the threshold of synaptic plasticity. Given the synaptic location of TRPV1 and its high Ca2+ permeability, we hypothesize that TRPV1 can modulate the threshold of LTP/LTD in the hippocampal CA1 area of rodent brain slice. Consistent with this idea, a recent report shows that TRPV1 knockout mice display decreased hippocampal LTP. However, whether TRPV1 activation by its ligands can modulate the threshold of LTP/LTD is still not known. In the present study we found that capsaicin enhanced LTP but reduced LTD as reflected by a leftward shift of the threshold for synaptic plasticity. In marked contrast, these capsaicin effects were absent after applying the antagonist of TRPV1 or using the TRPV1-KO mice. The behavioral stress is known to impair LTP, facilitate LTD and impair the retrieval of spatial memory, which effect seems opposite that of capsaicin. Therefore, we further investigate whether capsaicin can neutralize the effects of stress on LTP/LTD and on spatial memory retrieval. We found that capsaicin indeed neutralized the stress effects rapidly as indicated by normal LTP and no LTD in the stressed animals. Remarkably, either intra-hippocampal or i.g. application of capsaicin can rapidly overcome the stress effect on impairing spatial memory. This is the first evidence that capsaicin activated-TRPV1 not only modifies the threshold for synaptic plasticity but also effectively overcomes the stress effect on synaptic plasticity and spatial memory. These findings may stimulate the research for a potential therapeutic effect on the stress-associated mental disorders by consuming chili pepper.
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