title: Neurotrophin 3 induces structural and functional modification of synapses through distinct molecular mechanisms.
abstract: The mechanisms by which neurotrophins elicit long-term structural and functional changes of synapses are not known. We report the mechanistic separation of functional and structural synaptic regulation by neurotrophin 3 (NT-3), using the neuromuscular synapse as a model. Inhibition of cAMP response element (CRE)-binding protein (CREB)-mediated transcription blocks the enhancement of transmitter release elicited by NT-3, without affecting the synaptic varicosity of the presynaptic terminals. Further analysis indicates that CREB is activated through Ca(2+)/calmodulin-dependent kinase IV (CaMKIV) pathway, rather than the mitogen-activated protein kinase (MAPK) or cAMP pathway. In contrast, inhibition of MAPK prevents the NT-3-induced structural, but not functional, changes. Genetic and imaging experiments indicate that the small GTPase Rap1, but not Ras, acts upstream of MAPK activation by NT-3. Thus, NT-3 initiates parallel structural and functional modifications of synapses through the Rap1-MAPK and CaMKIV-CREB pathways, respectively. These findings may have implications in the general mechanisms of long-term synaptic modulation by neurotrophins.
authors.affiliation: Section on Neural Development and Plasticity, National Institute of Child Health and Human Development, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Je
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.forename: Jiangzheng
authors.initials: J
authors.lastname: Zhou
authors.forename: Bai
authors.initials: B
authors.lastname: Lu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004594:Electrophysiology; D004625:Embryo, Nonmammalian / Q000166:cytology; D005260:Female; D007124:Immunoenzyme Techniques; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000502:physiology*; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism*; D017729:Presynaptic Terminals; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology*; D014158:Transcription, Genetic; D014982:Xenopus laevis / Q000254:growth & development / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D020933:Neurotrophin 3; D000242:Cyclic AMP; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins