title: Neurotransmission selectively regulates synapse formation in parallel circuits in vivo.
abstract: Activity is thought to guide the patterning of synaptic connections in the developing nervous system. Specifically, differences in the activity of converging inputs are thought to cause the elimination of synapses from less active inputs and increase connectivity with more active inputs. Here we present findings that challenge the generality of this notion and offer a new view of the role of activity in synapse development. To imbalance neurotransmission from different sets of inputs in vivo, we generated transgenic mice in which ON but not OFF types of bipolar cells in the retina express tetanus toxin (TeNT). During development, retinal ganglion cells (RGCs) select between ON and OFF bipolar cell inputs (ON or OFF RGCs) or establish a similar number of synapses with both on separate dendritic arborizations (ON-OFF RGCs). In TeNT retinas, ON RGCs correctly selected the silenced ON bipolar cell inputs over the transmitting OFF bipolar cells, but were connected with them through fewer synapses at maturity. Time-lapse imaging revealed that this was caused by a reduced rate of synapse formation rather than an increase in synapse elimination. Similarly, TeNT-expressing ON bipolar cell axons generated fewer presynaptic active zones. The remaining active zones often recruited multiple, instead of single, synaptic ribbons. ON-OFF RGCs in TeNT mice maintained convergence of ON and OFF bipolar cells inputs and had fewer synapses on their ON arbor without changes to OFF arbor synapses. Our results reveal an unexpected and remarkably selective role for activity in circuit development in vivo, regulating synapse formation but not elimination, affecting synapse number but not dendritic or axonal patterning, and mediating independently the refinement of connections from parallel (ON and OFF) processing streams even where they converge onto the same postsynaptic cell.
authors.affiliation: Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri 63110, USA. KerschensteinerD@vision.wustl.edu
authors.forename: Daniel
authors.initials: D
authors.lastname: Kerschensteiner
authors.forename: Josh L
authors.initials: JL
authors.lastname: Morgan
authors.forename: Edward D
authors.initials: ED
authors.lastname: Parker
authors.forename: Renate M
authors.initials: RM
authors.lastname: Lewis
authors.forename: Rachel O L
authors.initials: RO
authors.lastname: Wong
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism; D051245:Retinal Bipolar Cells / Q000166:cytology / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D013744:Tetanus Toxin / Q000235:genetics / Q000378:metabolism; D000097806:GluK2 Kainate Receptor
chemical_list: D018698:Glutamic Acid; D018092:Kainic Acid Receptors; D013744:Tetanus Toxin; D000097806:GluK2 Kainate Receptor
references.citation: Nat Rev Neurosci. 2004 Oct;5(10):747-57
references.pmid: 15378035
references.citation: Cell. 2001 Apr 6;105(1):43-55
references.pmid: 11301001
references.citation: Curr Opin Neurobiol. 1999 Feb;9(1):79-87
references.pmid: 10072367
references.citation: Nature. 2005 Apr 21;434(7036):1022-6
references.pmid: 15846347
references.citation: Nat Neurosci. 2001 Sep;4(9):877-86
references.pmid: 11528418
references.citation: Nature. 2003 Jul 24;424(6947):426-30
references.pmid: 12879070
references.citation: J Neurosci. 1997 May 1;17(9):3014-23
references.pmid: 9096137
references.citation: J Neurophysiol. 1978 Mar;41(2):472-83
references.pmid: 650277
references.citation: Nat Neurosci. 2006 Jan;9(1):85-92
references.pmid: 16341211
references.citation: J Comp Neurol. 2005 Sep 12;490(1):72-84
references.pmid: 16041714
references.citation: J Comp Neurol. 2004 Jan 26;469(1):70-82
references.pmid: 14689473
references.citation: Network. 2001 May;12(2):199-213
references.pmid: 11405422
references.citation: Nature. 2003 Jul 24;424(6947):430-4
references.pmid: 12879071
references.citation: Neural Dev. 2008 Mar 26;3:8
references.pmid: 18366789
references.citation: J Comp Neurol. 1986 Dec 15;254(3):382-402
references.pmid: 3794013
references.citation: J Comp Neurol. 2007 Aug 20;503(6):803-14
references.pmid: 17570502
references.citation: Nature. 1992 Oct 29;359(6398):832-5
references.pmid: 1331807
references.citation: J Neurosci. 2008 Mar 5;28(10):2342-52
references.pmid: 18322081
references.citation: Nat Biotechnol. 2004 Dec;22(12):1567-72
references.pmid: 15558047
references.citation: J Neurosci. 2001 Jun 15;21(12):4310-7
references.pmid: 11404416
references.citation: J Neurosci. 2001 Aug 15;21(16):6105-14
references.pmid: 11487634
references.citation: Neuron. 1996 Sep;17(3):371-4
references.pmid: 8816700
references.citation: J Neurosci. 2003 Jan 15;23(2):518-29
references.pmid: 12533612
references.citation: Neuron. 2001 Jan;29(1):131-43
references.pmid: 11182086
references.citation: Nat Neurosci. 2004 Mar;7(3):254-60
references.pmid: 14758365
references.citation: Trends Neurosci. 2005 Jan;28(1):20-9
references.pmid: 15626493
references.citation: J Comp Neurol. 2009 Feb 20;512(6):814-24
references.pmid: 19067356