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The Journal of Neuroscience, December 14, 2005, 25(50):11719-11729; doi:10.1523/JNEUROSCI.4087-05.2005

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Cellular/Molecular
Distinct Mechanisms for Neurotrophin-3-Induced Acute and Long-Term Synaptic Potentiation

Hyun-Soo Je,^1,2 * Jianzheng Zhou,^1 * Feng Yang,¹ and Bai Lu¹

¹Section on Neural Development and Plasticity, National Institute of Child Health and Human Development, and Gene, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-3714, and ²Genetics Graduate Program, George Washington University, Washington, DC 20052

Although neurotrophins elicit both acute and long-term effects, it is unclear whether the two modes of action are mediated by the same or different mechanisms. Using neuromuscular junction (NMJ) as a model system, we identified three characteristic features required for long-term, but not acute, forms of synaptic modulation by neurotrophin-3 (NT-3): endocytosis of NT-3-receptor complex, activation of the PI3 kinase substrate Akt, and new protein synthesis. Long-term effects were eliminated when NT-3 was conjugated to a bead that was too large to be endocytosed or when dominant-negative dynamin was expressed in presynaptic neurons. Presynaptic inhibition of Akt also selectively prevented NT-3-mediated long-term effects. Blockade of protein translation by the mammalian target of rapamycin inhibitor rapamycin prevented the long-term structural and functional changes at the NMJ, without affecting the acute potentiation of synaptic transmission by NT-3. These results reveal fundamental differences between acute and long-term modulation by neurotrophins.

Key words: synaptogenesis; Xenopus; TrkC; internalization; synaptic plasticity; FM dye; synaptic varicosity

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Received May 31, 2005; revised November 2, 2005; accepted November 4, 2005.

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