Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1alpha

Neuron. 2007 Jun 7;54(5):801-12. doi: 10.1016/j.neuron.2007.05.020.

Abstract

Endocannabinoids (eCBs) have emerged as key activity-dependent signals that, by activating presynaptic cannabinoid receptors (i.e., CB1) coupled to G(i/o) protein, can mediate short-term and long-term synaptic depression (LTD). While the presynaptic mechanisms underlying eCB-dependent short-term depression have been identified, the molecular events linking CB1 receptors to LTD are unknown. Here we show in the hippocampus that long-term, but not short-term, eCB-dependent depression of inhibitory transmission requires presynaptic cAMP/PKA signaling. We further identify the active zone protein RIM1alpha as a key mediator of both CB1 receptor effects on the release machinery and eCB-dependent LTD in the hippocampus. Moreover, we show that eCB-dependent LTD in the amygdala and hippocampus shares major mechanistic features. These findings reveal the signaling pathway by which CB1 receptors mediate long-term effects of eCBs in two crucial brain structures. Furthermore, our results highlight a conserved mechanism of presynaptic plasticity in the brain.

Publication types

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

MeSH terms

  • Amygdala / drug effects
  • Amygdala / metabolism
  • Animals
  • Cannabinoid Receptor Modulators / pharmacology
  • Cannabinoid Receptor Modulators / physiology*
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Endocannabinoids*
  • GTP-Binding Proteins / metabolism*
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology
  • Neural Pathways / drug effects
  • Neural Pathways / metabolism
  • Organ Culture Techniques
  • Receptor, Cannabinoid, CB1 / drug effects
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology

Substances

  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Receptor, Cannabinoid, CB1
  • Rims1 protein, mouse
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • GTP-Binding Proteins