Novel Mouse Model Reveals Distinct Activity-Dependent and -Independent Contributions to Synapse Development

Hdl Handle:
http://hdl.handle.net/10675.2/633
Title:
Novel Mouse Model Reveals Distinct Activity-Dependent and -Independent Contributions to Synapse Development
Authors:
Pacifici, Pier Giorgio; Peter, Christoph; Yampolsky, Pessah; Koenen, Michael; McArdle, Joseph J.; Witzemann, Veit
Abstract:
The balanced action of both pre- and postsynaptic organizers regulates the formation of neuromuscular junctions (NMJ). The precise mechanisms that control the regional specialization of acetylcholine receptor (AChR) aggregation, guide ingrowing axons and contribute to correct synaptic patterning are unknown. Synaptic activity is of central importance and to understand synaptogenesis, it is necessary to distinguish between activity-dependent and activity-independent processes. By engineering a mutated fetal AChR subunit, we used homologous recombination to develop a mouse line that expresses AChR with massively reduced open probability during embryonic development. Through histological and immunochemical methods as well as electrophysiological techniques, we observed that endplate anatomy and distribution are severely aberrant and innervation patterns are completely disrupted. Nonetheless, in the absence of activity AChRs form postsynaptic specializations attracting motor axons and permitting generation of multiple nerve/muscle contacts on individual fibers. This process is not restricted to a specialized central zone of the diaphragm and proceeds throughout embryonic development. Phenotypes can be attributed to separate activity-dependent and -independent pathways. The correct patterning of synaptic connections, prevention of multiple contacts and control of nerve growth require AChR-mediated activity. In contrast, myotube survival and acetylcholine-mediated dispersal of AChRs are maintained even in the absence of AChR-mediated activity. Because mouse models in which acetylcholine is entirely absent do not display similar effects, we conclude that acetylcholine binding to the AChR initiates activity-dependent and activity-independent pathways whereby the AChR modulates formation of the NMJ.
Editors:
Mei, Lin
Citation:
PLoS One. 2011 Jan 31; 6(1):e16469
Issue Date:
31-Jan-2011
URI:
http://hdl.handle.net/10675.2/633
DOI:
10.1371/journal.pone.0016469
PubMed ID:
21305030
PubMed Central ID:
PMC3031568
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Neurology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorPacifici, Pier Giorgioen_US
dc.contributor.authorPeter, Christophen_US
dc.contributor.authorYampolsky, Pessahen_US
dc.contributor.authorKoenen, Michaelen_US
dc.contributor.authorMcArdle, Joseph J.en_US
dc.contributor.authorWitzemann, Veiten_US
dc.contributor.editorMei, Lin-
dc.date.accessioned2012-10-26T16:26:56Z-
dc.date.available2012-10-26T16:26:56Z-
dc.date.issued2011-01-31en_US
dc.identifier.citationPLoS One. 2011 Jan 31; 6(1):e16469en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid21305030en_US
dc.identifier.doi10.1371/journal.pone.0016469en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/633-
dc.description.abstractThe balanced action of both pre- and postsynaptic organizers regulates the formation of neuromuscular junctions (NMJ). The precise mechanisms that control the regional specialization of acetylcholine receptor (AChR) aggregation, guide ingrowing axons and contribute to correct synaptic patterning are unknown. Synaptic activity is of central importance and to understand synaptogenesis, it is necessary to distinguish between activity-dependent and activity-independent processes. By engineering a mutated fetal AChR subunit, we used homologous recombination to develop a mouse line that expresses AChR with massively reduced open probability during embryonic development. Through histological and immunochemical methods as well as electrophysiological techniques, we observed that endplate anatomy and distribution are severely aberrant and innervation patterns are completely disrupted. Nonetheless, in the absence of activity AChRs form postsynaptic specializations attracting motor axons and permitting generation of multiple nerve/muscle contacts on individual fibers. This process is not restricted to a specialized central zone of the diaphragm and proceeds throughout embryonic development. Phenotypes can be attributed to separate activity-dependent and -independent pathways. The correct patterning of synaptic connections, prevention of multiple contacts and control of nerve growth require AChR-mediated activity. In contrast, myotube survival and acetylcholine-mediated dispersal of AChRs are maintained even in the absence of AChR-mediated activity. Because mouse models in which acetylcholine is entirely absent do not display similar effects, we conclude that acetylcholine binding to the AChR initiates activity-dependent and activity-independent pathways whereby the AChR modulates formation of the NMJ.en_US
dc.rightsPacifici et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectBiochemistryen_US
dc.subjectNeurochemistryen_US
dc.subjectNeurochemicalsen_US
dc.subjectAcetylcholineen_US
dc.subjectProteinsen_US
dc.subjectAcetylcholine Receptorsen_US
dc.subjectDevelopmental Biologyen_US
dc.subjectEmbryologyen_US
dc.subjectMolecular Developmenten_US
dc.subjectModel Organismsen_US
dc.subjectAnimal Modelsen_US
dc.subjectMouseen_US
dc.subjectNeuroscienceen_US
dc.subjectDevelopmental Neuroscienceen_US
dc.subjectAxon Guidanceen_US
dc.subjectNeurochemistryen_US
dc.subjectNeurochemicalsen_US
dc.subjectAcetylcholineen_US
dc.subjectNeurophysiologyen_US
dc.subjectNeuromuscular Junctionen_US
dc.subjectSynapsesen_US
dc.subjectMolecular Neuroscienceen_US
dc.subjectMotor Systemsen_US
dc.subjectNeurotransmittersen_US
dc.titleNovel Mouse Model Reveals Distinct Activity-Dependent and -Independent Contributions to Synapse Developmenten_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3031568en_US
dc.contributor.corporatenameDepartment of Neurology-
dc.contributor.corporatenameCollege of Graduate Studies-

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