Retrograde Endocannabinoid Regulation of GABAergic Inhibition in the Rat Dentate Gyrus Granule Cell

J Physiol. 2005 Sep 15;567(Pt 3):1001-10. doi: 10.1113/jphysiol.2005.094219. Epub 2005 Jul 21.


The dentate gyrus is a key input gateway for the hippocampus, and dentate function is potently regulated by GABAergic inhibition. GABAergic inhibition is plastic and modulated by many factors. Cytoplasmic calcium ([Ca(+)](i)) is one of these factors, and its elevation inhibits GABA-mediated transmission in the hippocampus including the dentate gyrus granule cells (DGCs). We examined whether the [Ca(+)](i)-dependent decrease of GABA(A) receptor-mediated inhibitory postsynaptic current (IPSC) is explained by the retrograde suppression of GABA release caused by the depolarization-induced elevation of [Ca(+)](i) in DGCs (DSI: depolarization-induced suppression of inhibition). Repeated brief depolarizations or a single long depolarization inhibited spontaneous IPSCs with amplitudes over 25 pA for up to a minute, and reduced the amplitude of IPSCs evoked by direct stimulation in the molecular layer, suggesting that DGCs are susceptible to DSI. The magnitude of DSI correlated linearly with the duration of depolarization, and so did the increase of [Ca(+)](i). DSI was blocked by intrapipette application of BAPTA. In addition, bath application of thapsigargin and ryanodine, and intrapipette application of ryanodine and ruthenium red reduced the [Ca(+)](i) increase caused by the DSI-inducing depolarization, and substantially reduced the magnitude of DSI. Finally, the cannabinoid receptor agonists, CP55,942 and WIN55,212-2, mimicked DSI and prevented further IPSC reduction by DSI. DSI was blocked by the antagonist, SR141716A. We conclude that GABAergic inhibition in DGCs is subject to endogenous cannabinoid (eCB)-mediated retrograde regulation, and this process involves a depolarization-initiated release of Ca(+) from ryanodine-sensitive stores. Our findings suggest eCBs probably have physiological functions in the regulation of GABAergic plasticity in the dentate gyrus.

MeSH terms

  • Animals
  • Benzoxazines
  • Calcium / metabolism
  • Dentate Gyrus / physiology*
  • Electrophysiology
  • Enzyme Inhibitors / pharmacology
  • GABA-A Receptor Antagonists*
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Patch-Clamp Techniques
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Receptors, GABA-A / physiology
  • Rimonabant
  • Ryanodine / pharmacology
  • Synaptic Transmission / physiology
  • Thapsigargin / pharmacology
  • gamma-Aminobutyric Acid / metabolism


  • Benzoxazines
  • Enzyme Inhibitors
  • GABA-A Receptor Antagonists
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Receptors, GABA-A
  • Ryanodine
  • gamma-Aminobutyric Acid
  • Win 55212-2
  • Thapsigargin
  • Rimonabant
  • Calcium