title: Muscarinic receptors modulate dendrodendritic inhibitory synapses to sculpt glomerular output.
abstract: Cholinergic [acetylcholine (ACh)] axons from the basal forebrain innervate olfactory bulb glomeruli, the initial site of synaptic integration in the olfactory system. Both nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs) are expressed in glomeruli. The activation of nAChRs directly excites both mitral/tufted cells (MTCs) and external tufted cells (ETCs), the two major excitatory neurons that transmit glomerular output. The functional roles of mAChRs in glomerular circuits are unknown. We show that the restricted glomerular application of ACh causes rapid, brief nAChR-mediated excitation of both MTCs and ETCs in the mouse olfactory bulb. This excitation is followed by mAChR-mediated inhibition, which is blocked by GABAA receptor antagonists, indicating the engagement of periglomerular cells (PGCs) and/or short axon cells (SACs), the two major glomerular inhibitory neurons. Indeed, selective activation of glomerular mAChRs, with ionotropic GluRs and nAChRs blocked, increased IPSCs in MTCs and ETCs, indicating that mAChRs recruit glomerular inhibitory circuits. Selective activation of glomerular mAChRs in the presence of tetrodotoxin increased IPSCs in all glomerular neurons, indicating action potential-independent enhancement of GABA release from PGC and/or SAC dendrodendritic synapses. mAChR-mediated enhancement of GABA release also presynaptically suppressed the first synapse of the olfactory system via GABAB receptors on sensory terminals. Together, these results indicate that cholinergic modulation of glomerular circuits is biphasic, involving an initial excitation of MTC/ETCs mediated by nAChRs followed by inhibition mediated directly by mAChRs on PGCs/SACs. This may phasically enhance the sensitivity of glomerular outputs to odorants, an action that is consistent with recent in vivo findings.
authors: Department of Anatomy & Neurobiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201, and sliu003@umaryland.edu mshipley@umaryland.edu.
authors: Shaolin
authors: http://orcid.org/0000-0003-3351-8642
authors: S
authors: Liu
authors: Department of Anatomy & Neurobiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201, and.
authors: Zuoyi
authors: Z
authors: Shao
authors: Department of Anatomy & Neurobiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201, and.
authors: Adam
authors: A
authors: Puche
authors: Department of Neurobiology and Anatomy and Brain Institute, University of Utah, Salt Lake City, Utah 84112.
authors: Matt
authors: M
authors: Wachowiak
authors: Department of Neurobiology and Anatomy and Brain Institute, University of Utah, Salt Lake City, Utah 84112.
authors: Markus
authors: M
authors: Rothermel
authors: Department of Anatomy & Neurobiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201, and sliu003@umaryland.edu mshipley@umaryland.edu.
authors: Michael T
authors: MT
authors: Shipley
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000075402:Channelrhodopsins; D002795:Choline O-Acetyltransferase / Q000235:genetics; D018678:Cholinergic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009830:Olfactory Bulb / Q000166:cytology*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D000075402:Channelrhodopsins; D018678:Cholinergic Agents; D018377:Neurotransmitter Agents; D011976:Receptors, Muscarinic; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine
keywords: cholinergic modulation; dendrodendritic synapses; glomerular circuits; glomerular output; inhibitory interneurons; olfactory bulb