Neurotrophin 3 induces structural and functional modification of synapses through distinct molecular mechanisms.
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.
Je
Hyun-Soo
HS
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.
Yang
Feng
F
Zhou
Jiangzheng
J
Lu
Bai
B
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*
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