title: Metabotropic suppression of excitation in murine autaptic hippocampal neurons.
abstract: Depolarization-induced suppression of excitation (DSE) and inhibition (DSI) are forms of short-term neuronal plasticity involving postsynaptic release of an endocannabinoid and the activation of presynaptic cannabinoid CB1 receptors. We have recently reported that CB1-dependent DSE can be elicited in autaptic cultures of excitatory hippocampal neurons of the mouse. We now report that the same preparation exhibits a parallel G(q)-coupled receptor-dependent production of endocannabinoids causing retrograde inhibition, also via CB1 receptors, which we will refer to as metabotropic suppression of excitation (MSE). We tested a spectrum of G(q)-coupled receptor agonists and found that both muscarinic and metabotropic glutamate receptors (group I) mediate retrograde inhibition via CB1 receptors in autaptic hippocampal neurons. Thus these neurons possess not only the pre- and postsynaptic machinery necessary for DSE but also that for MSE. This permitted a closer examination of MSE and its interaction with other aspects of the endocannabinoid retrograde signalling machinery: MSE mimics and occludes DSE and is itself occluded by the endocannabinoid 2-arachidonoyl glycerol (2-AG), consistent with 2-AG as a likely mediator of MSE. In contrast to DSE, MSE undergoes heterologous desensitization over the time course of minutes. In keeping with data reported for metabotropic suppression of inhibition (MSI) and DSI in the hippocampus, subthreshold MSE and DSE act synergistically. We additionally found that Delta9-tetrahydrocannabinol, which has been shown to attenuate DSE, antagonizes MSE. Finally, we have distinguished a neuronal subpopulation that exhibits DSE and a differential complement of MSE-mediating Gq-coupled receptors, making possible contrasting studies of MSE. Autaptic endocannabinoid signalling is rich, robust and complex in a deceptively simple package, including a previously unreported postsynaptic mechanism of adaptation in addition to known presynaptic CB1 desensitization. These adaptive sites offer novel targets for modulation of endogenous cannabinoid signalling.
authors.affiliation: Department of Anaesthesiology, University of Washington, Seattle, WA 98195, USA. straiker@u.washington.edu
authors.forename: Alex
authors.initials: A
authors.lastname: Straiker
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D005989:Glycerides / Q000494:pharmacology; D006213:Hallucinogens / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000166:cytology / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000502:physiology*; D012183:Retrograde Degeneration / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D006213:Hallucinogens; D043884:Receptor, Cannabinoid, CB1; D018094:Receptors, Metabotropic Glutamate; D011976:Receptors, Muscarinic; D013759:Dronabinol; C094503:glyceryl 2-arachidonate; D043802:GTP-Binding Protein alpha Subunits, Gq-G11