The pyramidal neurons are the most numerous neuronal elements in the cerebral cortex and their axons comprise the major source of efferent cortical fibers. The activity of pyramidal neurons reflects the integration of synaptic inputs that arise from intrinsic and extrinsic sources. Although few in number, inhibitory GABAergic inputs to pyramidal neurons are critical for regulating pyramidal neuron activity. The GABAergic interneurons are diverse in their morphology and synaptic connectivity, and they innervate specific domains of pyramidal neurons to control action potential timing, the efficacy and integration of excitatory inputs, and synchronous network activity. Some GABAergic interneurons express the type-1 cannabinoid receptor (CB1R) on their synaptic terminals and pyramidal neurons are capable of producing and metabolizing endogenous ligands that activate CB1R (i.e., endocannabinoids). Therefore, we tested the hypothesis that endocannabinoids regulate GABAergic inhibition in the cortex by acting as retrograde signaling molecules between pyramidal neurons and a subpopulation of interneurons.; Using whole-cell patch clamp recordings from pyramidal neurons in slices of mouse cortex, we show that these cells can suppress afferent somatic inhibition via retrograde synaptic signaling. The retrograde signaling is initiated by pyramidal neuron depolarization and subsequent Ca2+ influx, and is expressed as a reduction in the probability of GABA release from the synaptic terminals of interneurons. This depolarization-induced suppression of inhibition, or DSI, is abolished by CB1R antagonists and occluded by a CB1R agonist, indicating that an endocannabinoid is the retrograde messenger. Furthermore, the subpopulation of interneurons involved in cortical DSI are excited by cholinergic activation and their axons selectively target the perisomatic membrane compartment of pyramidal neurons.; The specificity of endocannabinoid-mediated DSI suggests that the regulation of somatic inhibition is an important feature of cortical circuits. We believe that endocannabinoid signaling in the neocortex is involved in several aspects of synaptic integration and plasticity, and that DSI provides a mechanism enabling postsynaptic neurons to regulate afferent inhibition in an activity-dependent manner. Moreover, the similarity between cortical and hippocampal DSI indicates that this form of signaling is a conserved and universal feature of these complex brain systems.
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