| Motor neuron-specific overexpression of the presynaptic choline transporter: impact on motor endurance and evoked muscle activity. | |
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MedLine Citation:
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PMID: 20888396 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The presynaptic, hemicholinium-3 sensitive, high-affinity choline transporter (CHT) supplies choline for acetylcholine (ACh) synthesis. In mice, a homozygous deletion of CHT (CHT-/-) leads to premature cessation of spontaneous or evoked neuromuscular signaling and is associated with perinatal cyanosis and lethality within 1 h. Heterozygous (CHT+/-) mice exhibit diminished brain ACh levels and demonstrate an inability to sustain vigorous motor activity. We sought to explore the contribution of CHT gene dosage to motor function in greater detail using transgenic mice where CHT is expressed under control of the motor neuron promoter Hb9 (Hb9:CHT). On a CHT-/- background, the Hb9:CHT transgene conferred mice with the ability to move and breath for a postnatal period of ∼24 h, thus increasing survival. Conversely, Hb9:CHT expression on a wild-type background (CHT+/+;Hb9:CHT) leads to an increased capacity for treadmill running compared to wild-type littermates. Analysis of the stimulated compound muscle action potential (CMAP) in these animals under basal conditions established that CHT+/+;Hb9:CHT mice display an unexpected, bidirectional change, producing either elevated or reduced CMAP amplitude, relative to CHT+/+ animals. To examine whether these two groups arise from underlying changes in synaptic properties, we used high-frequency stimulation of motor axons to assess CMAP recovery kinetics. Although CHT+/+; Hb9:CHT mice in the two groups display an equivalent, time-dependent reduction in CMAP amplitude, animals with a higher basal CMAP amplitude demonstrate a significantly enhanced rate of recovery. To explain our findings, we propose a model whereby CHT support for neuromuscular signaling involves contributions to ACh synthesis as well as cholinergic synaptic vesicle availability. |
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Authors:
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D Lund; A M Ruggiero; S M Ferguson; J Wright; B A English; P A Reisz; S M Whitaker; A C Peltier; R D Blakely |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-10-01 |
Journal Detail:
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Title: Neuroscience Volume: 171 ISSN: 1873-7544 ISO Abbreviation: Neuroscience Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-24 Completed Date: 2011-03-10 Revised Date: 2011-12-30 |
Medline Journal Info:
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Nlm Unique ID: 7605074 Medline TA: Neuroscience Country: United States |
Other Details:
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Languages: eng Pagination: 1041-53 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetylcholine
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pharmacology Acetylcholinesterase / metabolism Action Potentials / genetics Animals Animals, Newborn Behavior, Animal Brain / cytology Choline O-Acetyltransferase / metabolism Electric Stimulation / methods Exercise Test / methods GPI-Linked Proteins / metabolism Gene Expression Regulation, Developmental / genetics Green Fluorescent Proteins / genetics Homeodomain Proteins / genetics Membrane Transport Proteins / genetics, metabolism* Mice Mice, Transgenic Motor Activity / genetics, physiology* Motor Neurons / cytology*, metabolism* Muscle, Skeletal / physiology Nerve Tissue Proteins Neuromuscular Junction / metabolism Statistics, Nonparametric Synapses / metabolism* Transcription Factors / genetics |
| Grant Support | |
ID/Acronym/Agency:
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MH073159/MH/NIMH NIH HHS; P01 HL056693-15/HL/NHLBI NIH HHS; R37 MH073159-08/MH/NIMH NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/GPI-Linked Proteins; 0/Homeodomain Proteins; 0/Membrane Transport Proteins; 0/Nerve Tissue Proteins; 0/Transcription Factors; 0/choline transporter; 0/enhanced green fluorescent protein; 140115-73-7/Hb9 protein, mouse; 147336-22-9/Green Fluorescent Proteins; 51-84-3/Acetylcholine; EC 2.3.1.6/Choline O-Acetyltransferase; EC 3.1.1.7/Acetylcholinesterase; EC 3.1.1.7/Ache protein, mouse |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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