Muscarinic signaling in the cochlea: presynaptic and postsynaptic effects on efferent feedback and afferent excitability.
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.
Maison
Stéphane F
SF
Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts 02115, USA. stephane_maison@meei.harvard.edu
Liu
Xiao-Ping
XP
Vetter
Douglas E
DE
Eatock
Ruth Anne
RA
Nathanson
Neil M
NM
Wess
Jürgen
J
Liberman
M Charles
MC
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
D012333:RNA, Messenger; D011976:Receptors, Muscarinic
Mol Cell Biol. 2007 Jun;27(12):4500-12
17438141
J Neurosci. 2001 Sep 15;21(18):7372-83
11549747
Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20594-9
18077337
J Neurophysiol. 2007 May;97(5):3269-78
17344378
Brain Res. 1999 Nov 6;846(2):196-203
10556636
Acta Otolaryngol. 1986 Sep-Oct;102(3-4):194-203
3490732
Pharmacol Ther. 1993 Jun;58(3):319-79
7504306
J Neurosci. 2006 Oct 4;26(40):10315-26
17021187
J Neurosci. 2002 Dec 15;22(24):10838-46
12486177
J Neurocytol. 1988 Oct;17(5):711-25
2463341
J Acoust Soc Am. 1983 Jul;74(1):115-23
6886194
Handb Exp Pharmacol. 2008;(184):207-60
18064416
Crit Rev Neurobiol. 1996;10(1):69-99
8853955
J Membr Biol. 2001 Aug 1;182(3):171-81
11547340
J Neurosci. 1997 Jan 1;17(1):428-37
8987768
Neuron. 2009 Jan 29;61(2):272-86
19186169
J Acoust Soc Am. 1970 Oct;48(4):950-65
5480390
Neuropharmacology. 2000 Oct;39(13):2515-24
11044723
Hear Res. 1983 Jan;9(1):113-21
6826463
Hear Res. 1996 May;95(1-2):87-99
8793511
J Assoc Res Otolaryngol. 2002 Sep;3(3):248-68
12382101
Physiol Rev. 1993 Apr;73(2):309-73
8097330
Hear Res. 1994 Apr;74(1-2):135-47
8040084
Brain Res Mol Brain Res. 1996 Aug;40(1):127-35
8840020
Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13311-6
9371842
PLoS Biol. 2009 Jan 20;7(1):e18
19166271
Proc Biol Sci. 1991 May 22;244(1310):161-7
1679550
J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2002 Jun;188(5):381-95
12073083
Brain Res. 1993 Oct 29;626(1-2):200-9
8281431
J Neurosci. 1992 Mar;12(3):800-9
1545240
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):14096-101
11707605
Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1692-7
9990086
J Neurochem. 1992 Aug;59(2):765-7
1629746
Cell. 2006 Oct 20;127(2):277-89
17055430
Brain Res. 1979 Sep 7;173(1):152-5
487078
Hear Res. 1980 Oct;3(3):189-204
7440423
Annu Rev Pharmacol Toxicol. 2004;44:423-50
14744253
J Neurophysiol. 2003 Nov;90(5):3178-200
14615429
Nat Neurosci. 2007 Oct;10(10):1238-40
17828255
J Assoc Res Otolaryngol. 2008 Dec;9(4):477-89
18688678
Neuroscience. 2002;111(2):291-302
11983315
J Physiol. 1993 Apr;463:227-44
7504105
Hear Res. 1992 Dec;64(1):1-5
1362722
Hear Res. 1992 Aug;61(1-2):106-16
1326504
Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10483-8
10468635
J Neurosci. 2002 Mar 1;22(5):1709-17
11880500
J Comp Neurol. 1996 Sep 09;373(1):27-40
8876460
J Neurophysiol. 2003 Nov;90(5):2941-9
12904337
Naunyn Schmiedebergs Arch Pharmacol. 2009 Apr;379(4):389-95
18974978
J Neurophysiol. 2005 Nov;94(5):3134-42
16222072
J Assoc Res Otolaryngol. 2001 Jun;2(2):118-29
11550522
Neurochem Int. 1995 Oct-Nov;27(4-5):301-11
8845730
Am J Physiol Cell Physiol. 2002 May;282(5):C1121-35
11940528
Cell. 1994 Nov 18;79(4):705-15
7954834
J Neurosci. 2005 Aug 24;25(34):7867-75
16120789
Hear Res. 2003 Nov;185(1-2):97-108
14599697
J Neurophysiol. 2007 Feb;97(2):1775-85
17093118
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3501-6
11248107
Hear Res. 1992 May;59(2):250-4
1319989
J Neurophysiol. 2007 Apr;97(4):2930-6
17267753
J Comp Neurol. 2003 Jan 13;455(3):406-16
12483691
J Physiol. 1991 Oct;442:669-90
1798048
J Neurosci. 1995 May;15(5 Pt 1):3667-78
7751937
J Neurosci. 1996 Apr 15;16(8):2574-84
8786433
Brain Res. 1988 Nov 22;474(1):185-8
3214711
Nature. 2001 Mar 8;410(6825):207-12
11242080
J Acoust Soc Am. 2003 Feb;113(2):914-24
12597185
Neuron. 1999 May;23(1):93-103
10402196
Nat Neurosci. 2006 Dec;9(12):1474-6
17115038