Involvement of cannabinoid CB1 receptor in associative learning and in hippocampal CA3-CA1 synaptic plasticity

Cereb Cortex. 2012 Mar;22(3):550-66. doi: 10.1093/cercor/bhr103. Epub 2011 Jun 14.


We studied, in behaving mice, the contribution of CB1 receptors to the activity-dependent changes induced at the hippocampal CA3-CA1 synapse by associative learning and following experimentally evoked long-term potentiation (LTP). Mice were classically conditioned to evoke eyelid responses with a trace paradigm using a tone as conditioned stimulus (CS) and an electric shock as unconditioned stimulus (US). Field excitatory postsynaptic potentials (fEPSPs) were evoked at the CA3-CA1 synapse during the CS-US interval across training. Conditioning was performed in presence of an agonist (WIN55,212-2) alone or with an antagonist (AM251) of the CB1 receptor, injected either systemically or locally. Conditioned responses (CRs) and fEPSP potentiation were depressed by WIN55,212-2. LTP was evoked by high-frequency stimulation of Schaffer collaterals after systemic or local WIN55,212-2 and AM251 injections. WIN55,212-2 affected the induction phase of LTP, mainly when injected locally. The addition of AM251 canceled out the effects of WIN55,212-2. Similar experiments were carried out in animals lacking the CB1 receptor (CB1(-/-) mice) and following silencing of hippocampal CB1 receptors (CB1R-siRNA-injected animals). In this case, CRs (CB1(-/-) mice) and LTP (CB1(-/-) and CB1R-siRNA-injected mice) reached lower values than their respective controls. Results offer new insights for understanding CB1 receptor contribution to associative learning and to CA3-CA1 synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Association Learning / physiology*
  • CA1 Region, Hippocampal / metabolism
  • CA1 Region, Hippocampal / physiology*
  • CA3 Region, Hippocampal / metabolism
  • CA3 Region, Hippocampal / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Pathways / metabolism
  • Neural Pathways / physiology
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology*
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / deficiency
  • Receptor, Cannabinoid, CB1 / physiology*
  • Synaptic Transmission / genetics
  • Synaptic Transmission / physiology*


  • Receptor, Cannabinoid, CB1