Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons.
Endocannabinoids are emerging as potent modulators of neuronal activity throughout the brain, and activation of the type-1 cannabinoid receptor (CB1R) reduces sensory-evoked cortical responses in vivo, presumably by decreasing excitatory transmission. In the neocortex, CB1R is differentially expressed across neocortical laminae, with highest levels of expression in layers 2/3 and 5. Although we have shown that cannabinoid signaling in layer 2/3 of somatosensory cortex targets both gamma-aminobutyric acid (GABA) and glutamate release, the predominant effect is a net increase in pyramidal neuron (PN) activity due to disinhibition. The role of endocannabinoid signaling in layer 5, the main output layer of the neocortex, remains unknown. We found that inducing activity in layer 5 PNs resulted in endocannabinoid-mediated depolarization-induced suppression of excitation (DSE), whereas the majority of inhibitory inputs were cannabinoid insensitive. Furthermore, in contrast to layer 2/3, the net effect of elevations in action potential firing of layer 5 PNs was an endocannabinoid-mediated decrease in PN spike probability. Interestingly, excitatory synaptic currents in layer 5 evoked by intralaminar stimulation were cannabinoid sensitive, whereas inputs evoked from layer 2/3 were insensitive, suggesting specificity of cannabinoid signaling across glutamatergic inputs. Thus, cannabinoids have differential effects on excitation and inhibition across cortical layers, and endocannabinoid signaling in layer 5 may serve to selectively decrease the efficacy of a subset of excitatory inputs.
Department of Pharmacology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Dale A
DA
Fortin
Eric S
ES
Levine
D000818:Animals; D048588:Benzoxazines; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D004594:Electrophysiology; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005971:Glutamates / Q000502:physiology*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000502:physiology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects*; D043884:Receptor, Cannabinoid, CB1 / Q000096:biosynthesis / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005971:Glutamates; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone