Gap junctions in olfactory neurons modulate olfactory sensitivity.
BACKGROUND
One of the fundamental questions in olfaction is whether olfactory receptor neurons (ORNs) behave as independent entities within the olfactory epithelium. On the basis that mature ORNs express multiple connexins, I postulated that gap junctional communication modulates olfactory responses in the periphery and that disruption of gap junctions in ORNs reduces olfactory sensitivity. The data collected from characterizing connexin 43 (Cx43) dominant negative transgenic mice OlfDNCX, and from calcium imaging of wild type mice (WT) support my hypothesis.


RESULTS
I generated OlfDNCX mice that express a dominant negative Cx43 protein, Cx43/β-gal, in mature ORNs to inactivate gap junctions and hemichannels composed of Cx43 or other structurally related connexins. Characterization of OlfDNCX revealed that Cx43/β-gal was exclusively expressed in areas where mature ORNs resided. Real time quantitative PCR indicated that cellular machineries of OlfDNCX were normal in comparison to WT. Electroolfactogram recordings showed decreased olfactory responses to octaldehyde, heptaldehyde and acetyl acetate in OlfDNCX compared to WT. Octaldehyde-elicited glomerular activity in the olfactory bulb, measured according to odor-elicited c-fos mRNA upregulation in juxtaglomerular cells, was confined to smaller areas of the glomerular layer in OlfDNCX compared to WT. In WT mice, octaldehyde sensitive neurons exhibited reduced response magnitudes after application of gap junction uncoupling reagents and the effects were specific to subsets of neurons.


CONCLUSIONS
My study has demonstrated that altered assembly of Cx43 or structurally related connexins in ORNs modulates olfactory responses and changes olfactory activation maps in the olfactory bulb. Furthermore, pharmacologically uncoupling of gap junctions reduces olfactory activity in subsets of ORNs. These data suggest that gap junctional communication or hemichannel activity plays a critical role in maintaining olfactory sensitivity and odor perception.
Zhang
Chunbo
C
Department of Biological, Chemical and Physical Sciences, Illinois Institute of Technology, Chicago, IL 60616, USA. zhangc@iit.edu
D000818:Animals; D015153:Blotting, Western; D001931:Brain Mapping; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics; D017630:Connexins / Q000096:biosynthesis / Q000235:genetics; D004594:Electrophysiology; D017629:Gap Junctions / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009812:Odorants; D009831:Olfactory Mucosa / Q000502:physiology; D018034:Olfactory Receptor Neurons / Q000378:metabolism / Q000502:physiology*; D020648:Peptide Elongation Factor 1 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012903:Smell / Q000502:physiology*; D001616:beta-Galactosidase / Q000235:genetics
D018031:Connexin 43; D017630:Connexins; D020648:Peptide Elongation Factor 1; D012333:RNA, Messenger; D001616:beta-Galactosidase; D002118:Calcium
Nat Rev Neurosci. 2002 Nov;3(11):884-95
12415296
Science. 2001 May 11;292(5519):1178-80
11349152
Eur J Neurosci. 2006 Jun;23(12):3176-86
16820008
Prog Biophys Mol Biol. 2007 May-Jun;94(1-2):120-43
17470375
J Biol Chem. 2008 Sep 26;283(39):26374-82
18676366
Pflugers Arch. 2004 Jul;448(4):363-75
15048573
J Physiol. 2001 Jan 1;530(Pt 1):113-22
11136863
J Cell Sci. 2001 Nov;114(Pt 22):4013-24
11739633
Trends Neurosci. 2002 Oct;25(10):487-9
12220868
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6436-41
17389364
Neuron. 2001 Aug 16;31(3):477-85
11516403
J Neurosci Res. 1996 Jan 15;43(2):146-60
8820963
Antioxid Redox Signal. 2009 Feb;11(2):369-99
18816186
J Cell Biol. 1995 Jul;130(2):419-29
7542247
J Neurosci. 2005 Jan 19;25(3):566-76
15659592
J Neurosci. 2006 Jan 25;26(4):1247-59
16436612
Biosystems. 2004 Jan;73(1):25-43
14729280
J Neurocytol. 2005 Sep;34(3-5):307-41
16841170
Dev Biol. 1998 Dec 1;204(1):224-34
9851855
Antioxid Redox Signal. 2009 Feb;11(2):283-95
18831677
Curr Med Chem. 2003 Oct;10(19):2045-58
12871102
Neuron. 2005 Jun 2;46(5):761-72
15924862
Commun Integr Biol. 2009 May;2(3):239-40
19641742
J Physiol. 2009 Dec 15;587(Pt 24):5899-906
19884319
Science. 2002 Apr 19;296(5567):503-7
11964472
Cell Commun Adhes. 2001;8(4-6):249-52
12064597
J Physiol. 1993 Aug;468:1-10
8254501
Pflugers Arch. 2008 Jun;456(3):519-27
18172602
J Physiol. 1998 Jul 15;510 ( Pt 2):429-40
9705994
J Neurosci. 2001 Apr 1;21(7):2481-7
11264322
PLoS One. 2007 Aug 08;2(8):e712
17684558
J Neurophysiol. 1974 Nov;37(6):1115-30
4548085
J Comp Neurol. 2007 Jul 1;503(1):1-34
17480025
Neuron. 1999 Jul;23(3):499-511
10433262
Biochem Biophys Res Commun. 1986 Jan 14;134(1):29-36
3947327
Annu Rev Neurosci. 1999;22:487-509
10202546
J Histochem Cytochem. 2003 Nov;51(11):1545-55
14566026
Brain Res Brain Res Rev. 1998 May;26(2-3):176-83
9651521
Am J Physiol Regul Integr Comp Physiol. 2000 Jul;279(1):R1-8
10896857
Biophys J. 2001 Sep;81(3):1406-18
11509355
Brain Res Brain Res Rev. 2003 Apr;42(1):23-32
12668289
J Comp Neurol. 2000 Jul 10;422(4):489-95
10861521
J Neurosci. 2003 Sep 10;23(23):8291-301
12967991
Curr Mol Med. 2009 Mar;9(2):186-94
19275626
PLoS One. 2009 Jun 30;4(6):e6090
19564917
Science. 1989 May 19;244(4906):790-5
2499043
J Comp Neurol. 1992 Nov 15;325(3):359-78
1332989
J Comp Neurol. 2001 Jul 30;436(3):351-62
11438935
Neuron. 2001 Nov 20;32(4):723-35
11719211
J Comp Neurol. 2005 Sep 12;490(1):29-39
16041717
J Neurosci. 2000 Jun 15;20(12):4721-31
10844041
Biophys J. 1989 Apr;55(4):755-68
2470428
Cell. 1997 Dec 12;91(6):833-43
9413992
Cell. 2000 Mar 17;100(6):611-8
10761927
J Neurosci. 2007 Jan 3;27(1):132-40
17202480
J Neurosci. 2000 Mar 15;20(6):2383-90
10704512
Chem Senses. 2003 Nov;28(9):807-15
14654449
Circ Res. 1997 May;80(5):708-19
9130452
J Neurocytol. 1979 Feb;8(1):1-18
438867
J Comp Neurol. 2000 Oct 9;426(1):1-12
10980480
Nat Neurosci. 2002 Nov;5(11):1194-202
12379859
J Neurosci Methods. 1985 Jul;14(2):77-90
3897728
J Gen Physiol. 1987 Jul;90(1):95-125
2442298
Glia. 2006 Nov 15;54(7):758-73
17006904
J Comp Neurol. 2003 May 12;459(4):426-39
12687708
Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1970-5
16446455
Biochim Biophys Acta. 2004 Mar 23;1662(1-2):96-101
15033581
Nat Neurosci. 2000 Dec;3(12):1248-55
11100145
Curr Biol. 1998 Jun 4;8(12):R431-3
9637917
Annu Rev Physiol. 1999;61:283-310
10099690
J Neurosci. 1993 Jan;13(1):300-12
8423476
Neuron. 2004 Apr 8;42(1):9-21
15066261
Brain Res. 2002 Mar 1;929(1):37-47
11852029
J Neurosci. 2002 Apr 15;22(8):3033-43
11943806
Proc Natl Acad Sci U S A. 1989 Nov;86(21):8565-9
2701951
J Neurosci Methods. 1999 Oct 15;92(1-2):31-40
10595701
Chem Senses. 2005 Sep;30(7):615-26
16141292
J Physiol. 1992 Jan;445:201-30
1380084
Microsc Res Tech. 2002 Aug 1;58(3):168-75
12203695
Mol Biol Cell. 2001 Apr;12(4):831-45
11294890
J Neurophysiol. 2000 Jul;84(1):575-80
10899229
Toxicol Appl Pharmacol. 2004 Sep 15;199(3):285-94
15364544
Prog Brain Res. 1991;89:97-122
1839074
J Neurosci. 2006 Feb 22;26(8):2269-77
16495454
Circ Res. 1995 Dec;77(6):1156-65
7586229
Neuron. 2002 Nov 14;36(4):703-12
12441058