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Published 18 December 2006. doi:10.1083/jcb.200603061
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 6, 1029-1042
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Article

Neurotrophin 3 induces structural and functional modification of synapses through distinct molecular mechanisms



Hyun-Soo Je1,3, Feng Yang1, Jiangzheng Zhou1, and Bai Lu1,2

1 Section on Neural Development and Plasticity, National Institute of Child Health and Human Development, and 2 Gene, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892
3 Genetics Graduate Program, George Washington University, Washington, DC 20052

Correspondence to Bai Lu: bailu{at}mail.nih.gov

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 Ca2+/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.

Abbreviations used in this paper: AChR, acetylcholine receptor; bZIP, basic leucine zipper; CAM, cell adhesion molecule; CaMK, calmodulin-dependent kinase; CRE, cAMP response element; CREB, CRE-binding protein; Dn, dominant-negative; ESC, evoked synaptic current; FRET, fluorescent resonance energy transfer; LTF, long-term facilitation; LTP, long-term potentiation; NMJ, neuromuscular junction; pCREB, phospho-CREB; PKA, protein kinase A; ROI, region of interest; SYP, synaptophysin.


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