A novel non-CB1/TRPV1 endocannabinoid-mediated mechanism depresses excitatory synapses on hippocampal CA1 interneurons

Hippocampus. 2012 Feb;22(2):209-21. doi: 10.1002/hipo.20884. Epub 2010 Nov 10.


Endocannabinoids (eCBs) mediate various forms of synaptic plasticity at excitatory and inhibitory synapses in the brain. The eCB anandamide binds to several receptors including the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1). We recently identified that TRPV1 is required for long-term depression at excitatory synapses on CA1 hippocampal stratum radiatum interneurons. Here we performed whole-cell patch clamp recordings from CA1 stratum radiatum interneurons in rat brain slices to investigate the effect of the eCB anandamide on excitatory synapses as well as the involvement of Group I metabotropic glutamate receptors (mGluRs), which have been reported to produce eCBs endogenously. Application of the nonhydrolysable anandamide analog R-methanandamide depressed excitatory transmission to CA1 stratum radiatum interneurons by ∼50%. The Group I mGluR agonist DHPG also depressed excitatory glutamatergic transmission onto interneurons to a similar degree, and this depression was blocked by the mGluR5 antagonist MPEP (10 μM) but not by the mGluR1 antagonist CPCCOEt (50 μM). Interestingly, however, neither DHPG-mediated nor R-methanandamide-mediated depression was blocked by the TRPV1 antagonist capsazepine (10 μM), the CB1 antagonist AM-251 (2 μM) or a combination of both, suggesting the presence of a novel eCB receptor or anandamide target at excitatory hippocampal synapses. DHPG also occluded R-methanandamide depression, suggesting the possibility that the two drugs elicit synaptic depression via a shared signaling mechanism. Collectively, this study illustrates a novel CB1/TRPV1-independent eCB pathway present in the hippocampus that mediates depression at excitatory synapses on CA1 stratum radiatum interneurons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / metabolism*
  • Arachidonic Acids / pharmacology
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / metabolism
  • Cannabinoid Receptor Modulators / metabolism
  • Cannabinoid Receptor Modulators / pharmacology
  • Endocannabinoids
  • Excitatory Postsynaptic Potentials
  • Interneurons / drug effects
  • Interneurons / metabolism*
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / physiology*
  • Patch-Clamp Techniques
  • Polyunsaturated Alkamides / metabolism*
  • Polyunsaturated Alkamides / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptors, Metabotropic Glutamate / metabolism
  • Signal Transduction / physiology
  • Synapses / drug effects
  • Synapses / metabolism*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • TRPV Cation Channels / metabolism


  • Arachidonic Acids
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1
  • Receptors, Metabotropic Glutamate
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • anandamide