title: Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum.
abstract: Endocannabinoids serve as retrograde messengers in many brain regions. These diffusible lipophilic molecules are released by postsynaptic cells and regulate presynaptic neurotransmitter release. Here we describe an additional mechanism that mediates the spread of endocannabinoid signaling to distant inhibitory synapses. Depolarization of cerebellar Purkinje cells reduced the firing rate of nearby interneurons, and this reduction in firing was blocked by the cannabinoid receptor antagonist AM251. The cannabinoid receptor agonist WIN55,212-2 also reduced firing rates in interneurons, and this inhibition arose from the activation of a small potassium conductance. Thus, endocannabinoids released from the dendrites of depolarized neurons can lead to inhibition of firing in nearby cells. Because interneurons can project over several hundred micrometers, this inhibition of firing allows cells to regulate synaptic inputs at distances well beyond the limits of endocannabinoid diffusion.
authors.affiliation: Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Anatol C
authors.initials: AC
authors.lastname: Kreitzer
authors.forename: Adam G
authors.initials: AG
authors.lastname: Carter
authors.forename: Wade G
authors.initials: WG
authors.lastname: Regehr
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D048588:Benzoxazines; D002121:Calcium Channel Blockers / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism*; D002525:Cerebellar Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004558:Electric Stimulation; D063388:Endocannabinoids; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011689:Purkinje Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D048588:Benzoxazines; D002121:Calcium Channel Blockers; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D026902:Potassium Channel Blockers; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone