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This Article Full Text Full Text (PDF) All Versions of this Article: 92/4/2105    most recent 00351.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Fortin, D. A. Articles by Levine, E. S. Search for Related Content PubMed PubMed Citation Articles by Fortin, D. A. Articles by Levine, E. S.

Brief Trains of Action Potentials Enhance Pyramidal Neuron Excitability Via Endocannabinoid-Mediated Suppression of Inhibition

Department of Pharmacology, University of Connecticut Health Center, Farmington, Connecticut 06030

Submitted 5 April 2004; accepted in final form 27 May 2004

Depolarization-induced suppression of inhibition (DSI) is a form of retrograde signaling at GABAergic synapses that is initiated by the calcium- and depolarization-dependent release of endocannabinoids from postsynaptic neurons. In the neocortex, pyramidal neurons (PNs) appear to use DSI as a mechanism for regulating somatic inhibition from a subpopulation of GABAergic inputs that express the type 1 cannabinoid receptor. Although postsynaptic control of afferent inhibition may directly influence the integrative properties of neocortical PNs, little is known about the patterns of activity that evoke endocannabinoid release and the impact such disinhibition may have on the excitability of PNs. Here we provide the first systematic survey of action potential (AP)-induced DSI in the neocortex. The magnitude and time course of DSI was directly related to the number and frequency of postsynaptic APs with significant suppression induced by a 20-Hz train containing as few as three APs. This AP-induced DSI was mediated by endocannabinoids as it was prevented by the cannabinoid receptor antagonist AM251 and potentiated by the endocannabinoid transport inhibitor AM404. We also explored the effects of endocannabinoid-mediated DSI on PN excitability. We found that single AP trains markedly increased PN responsiveness to excitatory synaptic inputs and promoted AP discharge by suppressing GABAergic inhibition. The time course of this effect paralleled DSI expression and was completely blocked by AM251. Taken together, our data suggest a role for endocannabinoids in regulating the output of cortical PNs.

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