title: Muscarinic receptor subtypes differentially control synaptic input and excitability of cerebellum-projecting medial vestibular nucleus neurons.
abstract: Neurons in the vestibular nuclei have a vital function in balance maintenance, gaze stabilization, and posture. Although muscarinic acetylcholine receptors (mAChRs) are expressed and involved in regulating vestibular function, it remains unclear how individual mAChR subtypes regulate vestibular neuronal activity. In this study, we determined which specific subtypes of mAChRs control synaptic input and excitability of medial vestibular nucleus (MVN) neurons that project to the cerebellum. Cerebellum-projecting MVN neurons were labeled by a fluorescent retrograde tracer and then identified in rat brainstem slices. Quantitative PCR analysis suggested that M2 and M3 were the possible major mAChR subtypes expressed in the MVN. The mAChR agonist oxotremorine-M significantly reduced the amplitude of glutamatergic excitatory post-synaptic currents evoked by stimulation of vestibular primary afferents, and this effect was abolished by the M2-preferring antagonist AF-DX 116. However, oxotremorine-M had no effect on GABA-mediated spontaneous inhibitory post-synaptic currents of labeled MVN neurons. Furthermore, oxotremorine-M significantly increased the firing activity of labeled MVN neurons, and this effect was blocked by the M3-preferring antagonist J104129 in most neurons tested. In addition, AF-DX 116 reduced the onset latency and prolonged the excitatory effect of oxotremorine-M on the firing activity of labeled MVN neurons. Our findings suggest that M3 is the predominant post-synaptic mAChR involved in muscarinic excitation of cerebellum-projecting MVN neurons. Pre-synaptic M2 mAChR regulates excitatory glutamatergic input from vestibular primary afferents, which in turn influences the excitability of cerebellum-projecting MVN neurons. This new information has important therapeutic implications for treating vestibular disorders with mAChR subtype-selective agents. Medial vestibular nucleus (MVN) neurons projecting to the cerebellum are involved in balance control. We found that activation of pre-synaptic M2 muscarinic receptors inhibit glutamatergic input from vestibular primary afferents, whereas stimulation of post-synaptic M3 muscarinic receptors increases the firing activity of cerebellum-projecting MVN neurons. This new information advances our understanding of the cholinergic mechanism regulating the vestibular system.
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.|Department of Otorhinolaryngology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
mesh_terms: D000475:Alkenes / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002531:Cerebellum / Q000166:cytology*; D018678:Cholinergic Agents / Q000494:pharmacology; D004347:Drug Interactions; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014726:Vestibular Nuclei / Q000166:cytology*
chemical_list: D000475:Alkenes; D018678:Cholinergic Agents; D058787:GABA-A Receptor Antagonists; C121300:J 104129; D010880:Piperidines; D011724:Pyridazines; D011976:Receptors, Muscarinic; D010890:Pirenzepine; C049853:gabazine; D010751:Phosphopyruvate Hydratase; C048593:otenzepad; D001640:Bicuculline
keywords: acetylcholine; brainstem; glutamate; muscarinic receptors; synaptic transmission; vestibular system
references.citation: Mol Pharmacol. 2006 Mar;69(3):1048-55
references.pmid: 16365281
references.citation: J Vestib Res. 2013;23(3):119-37
references.pmid: 24177345
references.citation: J Neurophysiol. 2007 Jan;97(1):102-9
references.pmid: 17050831
references.citation: J Neurochem. 2009 Jan;108(1):305-18
references.pmid: 19012737
references.citation: Mol Pharmacol. 2009 Dec;76(6):1279-89
references.pmid: 19726551
references.citation: Neurosci Lett. 2010 Jan 14;468(3):238-42
references.pmid: 19897014
references.citation: Neuroscience. 2001;102(1):159-66
references.pmid: 11226679
references.citation: J Neurosci. 2010 Mar 24;30(12):4460-6
references.pmid: 20335482
references.citation: J Biol Chem. 2010 Dec 24;285(52):40427-37
references.pmid: 20940295
references.citation: Neuroscience. 2011 Jan 13;172:494-509
references.pmid: 20971163
references.citation: J Vestib Res. 2011;21(1):33-47
references.pmid: 21422541
references.citation: Exp Brain Res. 2011 May;210(3-4):331-45
references.pmid: 21442224
references.citation: J Neurosci. 2011 Jul 27;31(30):10776-86
references.pmid: 21795530
references.citation: J Neurochem. 2011 Nov;119(3):594-603
references.pmid: 21883220
references.citation: Nat Rev Genet. 2012 Apr;13(4):227-32
references.pmid: 22411467
references.citation: Neurosci Lett. 1996 Oct 18;217(2-3):89-92
references.pmid: 8916079
references.citation: Pharmacol Rev. 1998 Jun;50(2):279-90
references.pmid: 9647869
references.citation: Anat Rec. 1998 Aug;251(4):431-8
references.pmid: 9713981
references.citation: Bioorg Med Chem Lett. 1999 Jul 19;9(14):2037-8
references.pmid: 10450976
references.citation: Brain Res. 1999 Sep 4;840(1-2):99-105
references.pmid: 10517957
references.citation: Ann N Y Acad Sci. 2005 Apr;1039:368-83
references.pmid: 15826990
references.citation: Brain Res. 2002 Apr 26;934(1):58-68
references.pmid: 11937070
references.citation: J Physiol. 2002 Sep 15;543(Pt 3):807-18
references.pmid: 12231640
references.citation: J Pharmacol Exp Ther. 2003 Feb;304(2):675-82
references.pmid: 12538821
references.citation: Life Sci. 2003 Mar 28;72(18-19):2047-54
references.pmid: 12628455
references.citation: Brain Res Bull. 2003 Jun 15;60(5-6):511-41
references.pmid: 12787870
references.citation: Trends Pharmacol Sci. 2003 Aug;24(8):414-20
references.pmid: 12915051
references.citation: Ann N Y Acad Sci. 2003 Oct;1004:169-82
references.pmid: 14662457
references.citation: J Physiol. 2004 Jan 1;554(Pt 1):100-10
references.pmid: 14678495
references.citation: J Neurosci. 2004 Mar 3;24(9):2102-11
references.pmid: 14999061
references.citation: Brain Res. 1976 Apr 16;106(1):31-46
references.pmid: 1268711
references.citation: Brain Res. 1976 Aug 6;112(1):77-90
references.pmid: 947495
references.citation: Exp Brain Res. 1978 Apr 14;31(4):591-604
references.pmid: 350598
references.citation: Hear Res. 1983 Jan;9(1):113-21
references.pmid: 6826463
references.citation: Eur J Pharmacol. 1984 May 18;101(1-2):101-10
references.pmid: 6547676
references.citation: J Comp Neurol. 1985 May 1;235(1):1-25
references.pmid: 3989000
references.citation: J Pharmacol Exp Ther. 1988 May;245(2):419-25
references.pmid: 3284995
references.citation: Neurosci Lett. 1988 Nov 11;93(2-3):231-5
references.pmid: 3241648
references.citation: Neurosci Lett. 1989 Nov 20;106(1-2):205-10
references.pmid: 2586827
references.citation: Exp Brain Res. 1990;79(3):547-63
references.pmid: 1971225
references.citation: Exp Brain Res. 1990;82(2):254-62
references.pmid: 1981039
references.citation: Acta Otolaryngol. 1991;111(1):27-35
references.pmid: 2014755
references.citation: J Neurosci Methods. 1991 Apr;37(2):121-31
references.pmid: 1908929
references.citation: Brain Res. 1991 Aug 23;557(1-2):1-4
references.pmid: 1747743
references.citation: Synapse. 1992 Apr;10(4):349-58
references.pmid: 1585263
references.citation: J Comp Neurol. 1993 Jan 22;327(4):521-34
references.pmid: 7680050
references.citation: Neuroscience. 1993 May;54(2):545-51
references.pmid: 7687755
references.citation: Pharmacol Ther. 1993 Jun;58(3):319-79
references.pmid: 7504306
references.citation: Brain Res. 1994 Oct 3;659(1-2):287-91
references.pmid: 7820677
references.citation: Brain Res Bull. 1995;36(5):443-52
references.pmid: 7712206
references.citation: FASEB J. 1995 May;9(8):619-25
references.pmid: 7768353
references.citation: Cell Biol Int. 1996 Mar;20(3):187-92
references.pmid: 8673067
references.citation: Acta Otolaryngol Suppl. 1995;520 Pt 1:164-9
references.pmid: 8749109
references.citation: Nat Rev Neurosci. 2012 May;13(5):308-24
references.pmid: 22498899
references.citation: J Stroke Cerebrovasc Dis. 2014 May-Jun;23(5):1148-56
references.pmid: 24268101
references.citation: J Biol Chem. 2014 May 16;289(20):14321-30
references.pmid: 24695732
references.citation: Curr Opin Neurol. 2015 Feb;28(1):83-8
references.pmid: 25502048
references.citation: J Neurophysiol. 2006 May;95(5):3086-96
references.pmid: 16467418