Neuregulin expression at neuromuscular synapses is modulated by synaptic activity and neurotrophic factors.
The proper formation of neuromuscular synapses requires ongoing synaptic activity that is translated into complex structural changes to produce functional synapses. One mechanism by which activity could be converted into these structural changes is through the regulated expression of specific synaptic regulatory factors. Here we demonstrate that blocking synaptic activity with curare reduces synaptic neuregulin expression in a dose-dependent manner yet has little effect on synaptic agrin or a muscle-derived heparan sulfate proteoglycan. These changes are associated with a fourfold increase in number and a twofold reduction in average size of synaptic acetylcholine receptor clusters that appears to be caused by excessive axonal sprouting with the formation of new, smaller acetylcholine receptor clusters. Activity blockade also leads to threefold reductions in brain-derived neurotrophic factor and neurotrophin 3 expression in muscle without appreciably changing the expression of these same factors in spinal cord. Adding back these or other neurotrophic factors restores synaptic neuregulin expression and maintains normal end plate band architecture in the presence of activity blockade. The expression of neuregulin protein at synapses is independent of spinal cord and muscle neuregulin mRNA levels, suggesting that neuregulin accumulation at synapses is independent of transcription. These findings suggest a local, positive feedback loop between synaptic regulatory factors that translates activity into structural changes at neuromuscular synapses.
Loeb
Jeffrey A
JA
Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. jloeb@med.wayne.edu
Hmadcha
Abdelkrim
A
Fischbach
Gerald D
GD
Land
Susan J
SJ
Zakarian
Vaagn L
VL
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D002642:Chick Embryo; D003472:Curare / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D020880:Neuregulins / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism*; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020880:Neuregulins; D003473:Neuromuscular Nondepolarizing Agents; D020933:Neurotrophin 3; D018733:Nicotinic Antagonists; D012333:RNA, Messenger; D003472:Curare