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1 Pharmacology, University of Connecticut Health Center, Farmington, CT, USA
* To whom correspondence should be addressed. E-mail: eslevine{at}neuron.uchc.edu.
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 regarding 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 AP-induced DSI in the neocortex. The magnitude and time course of DSI was directly related to the number and frequency of postsynaptic APs and was enhanced in the presence of the cholinergic receptor agonist carbachol. 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 consequences of neocortical DSI on PN excitability by examining the responsiveness of PNs to evoked synaptic stimulation. We found that endocannabinoid-mediated DSI markedly increased PN responsiveness to excitatory synaptic inputs and promoted AP discharge with a time course that paralleled DSI expression. Taken together, our data suggest a role for endocannabinoids in regulating the output of cortical PNs.
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