Synaptic plasticity: A depressing TRP

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Katherine Whalley

The transient receptor potential (TRP) family of ion channels has become one of the hottest areas of research; however, little is known about these channels' function in the brain. Kauer and colleagues now reveal that one family member, TRPV1, has a role in a particular form of synaptic plasticity, long-term depression (LTD), in the hippocampus.

The authors' discovery of this new role for TRPV1 was unexpected. They set out to characterize the LTD at excitatory synapses on hippocampal interneurons that follows high-frequency stimulation (HFS) of excitatory afferents. Using rat brain slices and electrophysiological techniques, they found that this form of LTD requires the activity of postsynaptic metabotropic glutamate receptors (mGluRs). At many synapses, mGluRs mediate LTD by releasing retrograde messengers that can act on presynaptic cannabinoid 1 (CB1) receptors to reduce glutamate release. However, blocking CB1 receptors did not prevent this form of LTD, suggesting that another mechanism was involved.

As TRPV1 is activated by many of the same retrograde messengers that signal through CB1 receptors, the authors investigated whether it might be involved in the observed LTD. Application of capsaicin, a specific TRPV1 agonist, mimicked the HFS-induced LTD, whereas the induction of LTD was prevented by the application of TRPV1 antagonists. Furthermore, in slices taken from Trpv1- /- mice, LTD could not be induced by HFS or capsaicin treatment. Application of capsaicin induced an inward current in wild-type hippocampal pyramidal cells but not in interneurons, indicating that the TRPV1 channels are not located on the postsynaptic interneuron but might be located in the presynaptic terminals of pyramidal cells.

Next, the authors sought to clarify whether the LTD involves the production of a retrograde messenger by the postsynaptic interneuron. Application of the arachidonic-acid metabolite 12-(S)-HPETE, which can be produced by activation of mGluRs, mimicked the LTD, an effect which was abolished when TRPV1 receptors were blocked or absent. Moreover, inhibiting endogenous 12-(S)-HPETE synthesis by blocking 12-lipoxygenase eliminated HFS-induced LTD. LTD was also eliminated when G-protein activity or Ca2+ levels in the postsynaptic cell were reduced, further suggesting that this cell is the source of the signal.

Much remains to be clarified about the pathways that link TRPV1 activation to reduced glutamate release. Nevertheless, this study provides the first evidence of a role for a TRP channel in synaptic plasticity. Importantly, the effects of TRPV1 activation were restricted to the excitatory synapses onto interneurons and did not extend to neighbouring synapses onto pyramidal cells, suggesting that the role of TRPV1 is synapse-specific. Future work might reveal a similar role for TRPV1 at other synaptic sites.

Nature Reviews Neuroscience 9, 324 (May 2008)