Multiple mechanisms of endocannabinoid response initiation in hippocampus

David A. Edwards, Jimok Kim, Bradley E. Alger

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Endocannabinoids (eCBs) act as retrograde messengers at inhibitory synapses of the hippocampal CA1 region. Current models place eCB synthesis in the postsynaptic pyramidal cell and the site of eCB action at cannabinoid receptors located on presynaptic interneuron terminals. Four responses at the CA1-interneuron synapse are attributed to eCBs: depolarization-induced suppression of inhibition (DSI), G-protein-coupled receptor-mediated enhancement of DSI (ΔDSI), persistent suppression of evoked inhibitory postsynaptic currents (eIPSCs), and finally, mGluR-dependent long-term depression (iLTD). It has been proposed that all are mediated by the eCB, 2-arachidonoyl glycerol, yet there is evidence that DSI does not arise from the same underlying biochemical processes as the other responses. In view of the increasing importance of eCB effects in the brain, it will be essential to understand the mechanisms by which eCB effects are produced. Our results reveal new differences in the biochemical pathways by which the eCB-dependent responses are initiated. Both U73122, a phospholipase C antagonist, and RHC-80267, a diacylglycerol (DAG) lipase antagonist, prevented eCB-dependent iLTD induction by 3,5-dihydroxyphenylglycine (DHPG). However, mAChR activation does not cause eCB-dependent iLTD. Neither enzyme inhibitor affects DSI, and persistent eCB-dependent eIPSC suppression induced by either mGluRs or mAChRs is unaffected by U73122. On the other hand, inhibition of DAG lipase prevents persistent eCB-dependent eIPSC suppression triggered by mAChRs. The results show that the biochemical pathways for the various eCB-dependent responses differ and might therefore be independently manipulated.

Original languageEnglish (US)
Pages (from-to)67-75
Number of pages9
JournalJournal of Neurophysiology
Volume95
Issue number1
DOIs
StatePublished - Jan 1 2006

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Endocannabinoids
Inhibitory Postsynaptic Potentials
Hippocampus
Lipoprotein Lipase
Interneurons
Synapses
Biochemical Phenomena
Hippocampal CA1 Region
Cannabinoid Receptors
Pyramidal Cells
Presynaptic Terminals
Type C Phospholipases
Enzyme Inhibitors
G-Protein-Coupled Receptors
Brain
1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology

Cite this

Multiple mechanisms of endocannabinoid response initiation in hippocampus. / Edwards, David A.; Kim, Jimok; Alger, Bradley E.

In: Journal of Neurophysiology, Vol. 95, No. 1, 01.01.2006, p. 67-75.

Research output: Contribution to journalArticle

Edwards, David A. ; Kim, Jimok ; Alger, Bradley E. / Multiple mechanisms of endocannabinoid response initiation in hippocampus. In: Journal of Neurophysiology. 2006 ; Vol. 95, No. 1. pp. 67-75.
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