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Neurotrophins as synaptic modulators

Nature Reviews Neuroscience volume 2, pages 2432 (2001) | Download Citation

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Abstract

The role of neurotrophins as regulatory factors that mediate the differentiation and survival of neurons has been well described. More recent evidence indicates that neurotrophins may also act as synaptic modulators. Here, I review the evidence that synaptic activity regulates the synthesis, secretion and action of neurotrophins, which can in turn induce immediate changes in synaptic efficacy and morphology. By this account, neurotrophins may participate in activity-dependent synaptic plasticity, linking synaptic activity with long-term functional and structural modification of synaptic connections.

Key points

  • Neurotrophins (NTs) are regulatory factors that mediate the differentiation and survival of neurons. Recent evidence indicates that NTs may also act as synaptic modulators.

  • Binding of an NT to a high-affinity tyrosine receptor kinase (Trk) initiates a signal-transduction cascade that can modify gene expression. Each Trk is preferentially activated by one or more NTs. A low-affinity pan-neurotrophin receptor (p75) forms a complex with the Trk receptor and modulates its activity.

  • After their synthesis in the cell body, NTs and Trks are transported in secretory granules and post-Golgi vesicles to the postsynaptic dendrites or presynaptic nerve terminals.

  • Synaptic activity may regulate the synthesis, packaging and transport of NTs and Trk receptors.

  • NT secretion also seems to be regulated by synaptic activity. NTs bind tightly to the cell surface or extracellular matrix after secretion and so are likely to act as highly localized synaptic modulators.

  • Here, a model for the synaptic actions of NTs is described:

  • Constitutive secretion of low levels of NTs from postsynaptic dendrites provides trophic regulation of synaptic functions, including the ability to generate long-term potentiation.

  • Transient high levels of postsynaptic calcium due to synaptic activity increase NT secretion, raising local levels of NTs. This may be supplemented by activity-dependent synthesis and transport of NTs.

  • Correlated synaptic activity can act cooperatively to raise the postsynaptic calcium concentration to a level sufficient to trigger high-level NT secretion.

  • High local NT levels then induce the modification of synaptic functions and the formation of new synaptic contacts.

  • Inputs with uncorrelated activity fail to raise the postsynaptic calcium concentration sufficiently and so may be deprived of NTs as a result of directed transport of NTs to adjacent synapses with correlated activity. This results in activity-dependent refinement of synaptic contacts.

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Acknowledgements

I thank A. Schinder and B. Benedikt for helpful discussions and comments. Work in the author's laboratory was supported by a grant from NIH.

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Affiliations

  1. Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3200 , USA. mpoo@uclink4.berkeley.edu

    • Mu-ming Poo

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Glossary

EPITOPE-TAGGED MOLECULE

A molecule labelled with the immunological determinant of an antigen for its subsequent localization with specific antibodies.

SYNAPTOSOMES

Discrete particles formed from the axon terminals upon brain homogenization, in which the main structural presynaptic features are preserved.

COLCHICINE

Alkaloid used to inhibit the polymerization of tubulin and cause the depolymerization of microtubules.

TETANUS TOXIN

Protein from Clostridium tetani that blocks synaptic exocytosis of specific synaptic vesicle proteins, such as synaptobrevin.

VERATRIDINE

Alkaloid that affects action potential generation by stabilizing sodium channels in the open state.

QUANTAL SIZE

The synaptic response elicited by a single vesicle of transmitter as determined by postsynaptic factors such as the number and affinity of receptors.

DOMINANT-NEGATIVE MOLECULE

A mutant molecule capable of interacting with the wild-type form to make an inactive complex.

FILOPODIA

Thin protrusions from a cell, which usually contain microfilaments.

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