Reduction in endocannabinoid tone is a homeostatic mechanism for specific inhibitory synapses

Nat Neurosci. 2010 May;13(5):592-600. doi: 10.1038/nn.2517. Epub 2010 Mar 28.

Abstract

When chronic alterations in neuronal activity occur, network gain is maintained by global homeostatic scaling of synaptic strength, but the stability of microcircuits can be controlled by unique adaptations that differ from the global changes. It is not understood how specificity of synaptic tuning is achieved. We found that, although a large population of inhibitory synapses was homeostatically scaled down after chronic inactivity, decreased endocannabinoid tone specifically strengthened a subset of GABAergic synapses that express cannabinoid receptors. In rat hippocampal slice cultures, a 3-5-d blockade of neuronal firing facilitated uptake and degradation of anandamide. The consequent reduction in basal stimulation of cannabinoid receptors augmented GABA release probability, fostering rapid depression of synaptic inhibition and on-demand disinhibition. This regulatory mechanism, mediated by activity-dependent changes in tonic endocannabinoid level, permits selective local tuning of inhibitory synapses in hippocampal networks.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Agatoxins
  • Animals
  • Arachidonic Acids / pharmacology
  • Benzamides / pharmacology
  • Benzoxazines / pharmacology
  • Biophysics
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology
  • Cannabinoid Receptor Modulators / metabolism*
  • Cannabinoid Receptor Modulators / pharmacology
  • Carbamates / pharmacology
  • Conotoxins / pharmacology
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Drug Interactions
  • Electric Stimulation / methods
  • Endocannabinoids*
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glycerides / pharmacology
  • Hippocampus / cytology
  • Homeostasis / drug effects
  • Homeostasis / physiology*
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Nerve Net / physiology
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology*
  • Neurons / drug effects
  • Neurons / physiology*
  • Patch-Clamp Techniques / methods
  • Piperidines / pharmacology
  • Polyamines / pharmacology
  • Polyunsaturated Alkamides / pharmacology
  • Pyrazoles / pharmacology
  • Rats
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism
  • Rimonabant
  • Sodium Channel Blockers / pharmacology
  • Synapses / drug effects
  • Synapses / physiology*
  • Tetrodotoxin / pharmacology
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Agatoxins
  • Arachidonic Acids
  • Benzamides
  • Benzoxazines
  • Calcium Channel Blockers
  • Cannabinoid Receptor Modulators
  • Carbamates
  • Conotoxins
  • Endocannabinoids
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Glycerides
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Polyamines
  • Polyunsaturated Alkamides
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Sodium Channel Blockers
  • cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
  • agatoxin-489
  • AM 251
  • Tetrodotoxin
  • gamma-Aminobutyric Acid
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • glyceryl 2-arachidonate
  • Rimonabant
  • Calcium
  • anandamide
  • N-(4-hydroxyphenyl)arachidonylamide