title: Muscarinic signaling in the cochlea: presynaptic and postsynaptic effects on efferent feedback and afferent excitability.
abstract: Acetylcholine is the major neurotransmitter of the olivocochlear efferent system, which provides feedback to cochlear hair cells and sensory neurons. To study the role of cochlear muscarinic receptors, we studied receptor localization with immunohistochemistry and reverse transcription-PCR and measured olivocochlear function, cochlear responses, and histopathology in mice with targeted deletion of each of the five receptor subtypes. M2, M4, and M5 were detected in microdissected immature (postnatal days 10-13) inner hair cells and spiral ganglion cells but not outer hair cells. In the adult (6 weeks), the same transcripts were found in microdissected organ of Corti and spiral ganglion samples. M2 protein was found, by immunohistochemistry, in olivocochlear fibers in both outer and inner hair cell areas. M3 mRNA was amplified only from whole cochleas, and M1 message was never seen in wild-type ears. Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were unaffected by loss of Gq-coupled receptors (M1, M3, or M5), as were shock-evoked olivocochlear effects and vulnerability to acoustic injury. In contrast, loss of Gi-coupled receptors (M2 and/or M4) decreased neural responses without affecting DPOAEs (at low frequencies). This phenotype and the expression pattern are consistent with excitatory muscarinic signaling in cochlear sensory neurons. At high frequencies, both ABRs and DPOAEs were attenuated by loss of M2 and/or M4, and the vulnerability to acoustic injury was dramatically decreased. This aspect of the phenotype and the expression pattern are consistent with a presynaptic role for muscarinic autoreceptors in decreasing ACh release from olivocochlear terminals during high-level acoustic stimulation and suggest that muscarinic antagonists could enhance the resistance of the inner ear to noise-induced hearing loss.
authors.affiliation: Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts 02115, USA. stephane_maison@meei.harvard.edu
authors.forename: Stéphane F
authors.initials: SF
authors.lastname: Maison
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Liu
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vetter
authors.forename: Ruth Anne
authors.initials: RA
authors.lastname: Eatock
authors.forename: Neil M
authors.initials: NM
authors.lastname: Nathanson
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: M Charles
authors.initials: MC
authors.lastname: Liberman
mesh_terms: D000818:Animals; D001309:Auditory Threshold / Q000502:physiology; D003051:Cochlea / Q000254:growth & development / Q000502:physiology*; D016057:Evoked Potentials, Auditory, Brain Stem; D025461:Feedback, Physiological; D005260:Female; D006199:Hair Cells, Auditory, Inner / Q000502:physiology; D018072:Hair Cells, Auditory, Outer / Q000502:physiology; D006317:Hearing Loss, Noise-Induced / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000502:physiology*; D009476:Neurons, Efferent / Q000502:physiology*; D017084:Otoacoustic Emissions, Spontaneous; D017729:Presynaptic Terminals / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D013136:Spiral Ganglion / Q000254:growth & development / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D011976:Receptors, Muscarinic
references.citation: Mol Cell Biol. 2007 Jun;27(12):4500-12
references.pmid: 17438141
references.citation: J Neurosci. 2001 Sep 15;21(18):7372-83
references.pmid: 11549747
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20594-9
references.pmid: 18077337
references.citation: J Neurophysiol. 2007 May;97(5):3269-78
references.pmid: 17344378
references.citation: Brain Res. 1999 Nov 6;846(2):196-203
references.pmid: 10556636
references.citation: Acta Otolaryngol. 1986 Sep-Oct;102(3-4):194-203
references.pmid: 3490732
references.citation: Pharmacol Ther. 1993 Jun;58(3):319-79
references.pmid: 7504306
references.citation: J Neurosci. 2006 Oct 4;26(40):10315-26
references.pmid: 17021187
references.citation: J Neurosci. 2002 Dec 15;22(24):10838-46
references.pmid: 12486177
references.citation: J Neurocytol. 1988 Oct;17(5):711-25
references.pmid: 2463341
references.citation: J Acoust Soc Am. 1983 Jul;74(1):115-23
references.pmid: 6886194
references.citation: Handb Exp Pharmacol. 2008;(184):207-60
references.pmid: 18064416
references.citation: Crit Rev Neurobiol. 1996;10(1):69-99
references.pmid: 8853955
references.citation: J Membr Biol. 2001 Aug 1;182(3):171-81
references.pmid: 11547340
references.citation: J Neurosci. 1997 Jan 1;17(1):428-37
references.pmid: 8987768
references.citation: Neuron. 2009 Jan 29;61(2):272-86
references.pmid: 19186169
references.citation: J Acoust Soc Am. 1970 Oct;48(4):950-65
references.pmid: 5480390
references.citation: Neuropharmacology. 2000 Oct;39(13):2515-24
references.pmid: 11044723
references.citation: Hear Res. 1983 Jan;9(1):113-21
references.pmid: 6826463
references.citation: Hear Res. 1996 May;95(1-2):87-99
references.pmid: 8793511
references.citation: J Assoc Res Otolaryngol. 2002 Sep;3(3):248-68
references.pmid: 12382101
references.citation: Physiol Rev. 1993 Apr;73(2):309-73
references.pmid: 8097330
references.citation: Hear Res. 1994 Apr;74(1-2):135-47
references.pmid: 8040084
references.citation: Brain Res Mol Brain Res. 1996 Aug;40(1):127-35
references.pmid: 8840020
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13311-6
references.pmid: 9371842
references.citation: PLoS Biol. 2009 Jan 20;7(1):e18
references.pmid: 19166271
references.citation: Proc Biol Sci. 1991 May 22;244(1310):161-7
references.pmid: 1679550
references.citation: J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2002 Jun;188(5):381-95
references.pmid: 12073083
references.citation: Brain Res. 1993 Oct 29;626(1-2):200-9
references.pmid: 8281431
references.citation: J Neurosci. 1992 Mar;12(3):800-9
references.pmid: 1545240
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):14096-101
references.pmid: 11707605
references.citation: Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1692-7
references.pmid: 9990086
references.citation: J Neurochem. 1992 Aug;59(2):765-7
references.pmid: 1629746
references.citation: Cell. 2006 Oct 20;127(2):277-89
references.pmid: 17055430
references.citation: Brain Res. 1979 Sep 7;173(1):152-5
references.pmid: 487078
references.citation: Hear Res. 1980 Oct;3(3):189-204
references.pmid: 7440423
references.citation: Annu Rev Pharmacol Toxicol. 2004;44:423-50
references.pmid: 14744253
references.citation: J Neurophysiol. 2003 Nov;90(5):3178-200
references.pmid: 14615429
references.citation: Nat Neurosci. 2007 Oct;10(10):1238-40
references.pmid: 17828255
references.citation: J Assoc Res Otolaryngol. 2008 Dec;9(4):477-89
references.pmid: 18688678
references.citation: Neuroscience. 2002;111(2):291-302
references.pmid: 11983315
references.citation: J Physiol. 1993 Apr;463:227-44
references.pmid: 7504105
references.citation: Hear Res. 1992 Dec;64(1):1-5
references.pmid: 1362722
references.citation: Hear Res. 1992 Aug;61(1-2):106-16
references.pmid: 1326504
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10483-8
references.pmid: 10468635
references.citation: J Neurosci. 2002 Mar 1;22(5):1709-17
references.pmid: 11880500
references.citation: J Comp Neurol. 1996 Sep 09;373(1):27-40
references.pmid: 8876460
references.citation: J Neurophysiol. 2003 Nov;90(5):2941-9
references.pmid: 12904337
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2009 Apr;379(4):389-95
references.pmid: 18974978
references.citation: J Neurophysiol. 2005 Nov;94(5):3134-42
references.pmid: 16222072
references.citation: J Assoc Res Otolaryngol. 2001 Jun;2(2):118-29
references.pmid: 11550522
references.citation: Neurochem Int. 1995 Oct-Nov;27(4-5):301-11
references.pmid: 8845730
references.citation: Am J Physiol Cell Physiol. 2002 May;282(5):C1121-35
references.pmid: 11940528
references.citation: Cell. 1994 Nov 18;79(4):705-15
references.pmid: 7954834
references.citation: J Neurosci. 2005 Aug 24;25(34):7867-75
references.pmid: 16120789
references.citation: Hear Res. 2003 Nov;185(1-2):97-108
references.pmid: 14599697
references.citation: J Neurophysiol. 2007 Feb;97(2):1775-85
references.pmid: 17093118
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3501-6
references.pmid: 11248107
references.citation: Hear Res. 1992 May;59(2):250-4
references.pmid: 1319989
references.citation: J Neurophysiol. 2007 Apr;97(4):2930-6
references.pmid: 17267753
references.citation: J Comp Neurol. 2003 Jan 13;455(3):406-16
references.pmid: 12483691
references.citation: J Physiol. 1991 Oct;442:669-90
references.pmid: 1798048
references.citation: J Neurosci. 1995 May;15(5 Pt 1):3667-78
references.pmid: 7751937
references.citation: J Neurosci. 1996 Apr 15;16(8):2574-84
references.pmid: 8786433
references.citation: Brain Res. 1988 Nov 22;474(1):185-8
references.pmid: 3214711
references.citation: Nature. 2001 Mar 8;410(6825):207-12
references.pmid: 11242080
references.citation: J Acoust Soc Am. 2003 Feb;113(2):914-24
references.pmid: 12597185
references.citation: Neuron. 1999 May;23(1):93-103
references.pmid: 10402196
references.citation: Nat Neurosci. 2006 Dec;9(12):1474-6
references.pmid: 17115038