Key Points
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In the central nervous system (CNS), the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4) were initially characterized for their ability to support neuronal survival and differentiation. However, recent evidence supports further roles for these factors in synapse formation, maturation and stabilization.
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The neurotrophins bind to two types of receptor: the Trk (tropomyosin receptor kinase) receptors and the p75 receptor. NGF is the preferred ligand for TrkA, BDNF and NT4 bind preferentially to TrkB, and NT3 to TrkC. They can all bind to p75, but it has not been shown clearly whether this receptor is involved in central synapse development.
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Neurotrophins could act at several levels to regulate synapse number: by promoting synaptogenesis and/or stabilizing existing synapses, and by influencing the maturation of developing synapses. These mechanisms have all been demonstrated experimentally, both for excitatory and for inhibitory synapses.
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Neurotrophins regulate synaptic vesicle dynamics through different mechanisms in the hippocampus and cerebellum. In the hippocampus, targeted deletion of Bdnf decreases the number of docked vesicles, whereas in the cerebellum, it augments the number of synaptic vesicles that are distant from the active zone. In both cases, the net effect is impaired function of the presynaptic terminal.
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The structural effects of neurotrophins at the presynaptic terminal also have functional correlates; for example, the increase in the pool of docked synaptic vesicles is essential for rapid synaptic transmission in the hippocampus. Functional properties, such as high-frequency stimulation and paired-pulse facilitation, are impaired in hippocampal and cerebellar synapses of Bdnf-knockout mice.
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Neurotrophins might regulate the SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) proteins, which control neurotransmitter release. The maturation of the neurotransmitter-release machinery has a prominent role in the transformation of immature synaptic contacts into mature functional synapses. The neurotrophins might also regulate signalling events at the postsynaptic terminal by controlling the surface expression of neurotransmitter receptors.
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Neurotrophins might control neuronal circuit formation and maturation by activity-independent mechanisms, as well as by interacting with activity-dependent processes.
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Further studies will be required to elucidate the cellular and molecular mechanisms that mediate the actions of neurotrophins at synapses, and to understand the biological responses to different neurotrophins in excitatory versus inhibitory neurons.
Abstract
The neurotrophins are best known for their ability to support neuronal survival and differentiation, but a role in synapse formation and plasticity has recently emerged. For central neurons, brain-derived neurotrophic factor can increase the number of excitatory and inhibitory synapses by regulating axonal morphology or by directly promoting synapse formation. In addition, neurotrophins promote the maturation and stabilization of the cellular and molecular components that are responsible for neurotransmitter release, and this ultimately leads to an increase in the number of functional synapses. These long-term structural and molecular changes are likely to be crucial not only during development, but also during synaptic plasticity in the adult.
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Acknowledgements
We are grateful to M. E. Rubio, F. de Pablo and E. J. de la Rosa for comments on the manuscript. C.V.-A. is an investigator of the Programa Ramón y Cajal.
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Glossary
- AUTOCRINE
-
Describes an agent that acts on the cell that produced it.
- PARACRINE
-
Describes a mechanism of signalling between cells that relies on the diffusion of signalling molecules through the intercellular spaces.
- OCULAR DOMINANCE COLUMN
-
One of a series of interdigitating bundles of axonal fibres in the visual cortex, containing afferents that represent one or other of the eyes.
- GREEN FLUORESCENT PROTEIN
-
(GFP). A fluorescent protein that was originally isolated from the jellyfish Aequorea victoria. It can be genetically conjugated with proteins to mark them. The most widely used mutant, enhanced GFP, is excited at 488 nm and has an emission maximum at 510 nm.
- PARALLEL FIBRES
-
Branches of the ascending axons of cerebellar granule cells. In the molecular layer of the cerebellar cortex, they run perpendicular to the planar Purkinje cell dendrites, with which they form so-called en passant synapses.
- PURKINJE CELLS
-
Inhibitory neurons in the cerebellum that uses GABA as its neurotransmitter. Their cell bodies are situated beneath the molecular layer, and their dendrites branch extensively in this layer. Their axons project into the underlying white matter, and they provide the only output from the cerebellar cortex.
- DOCKED VESICLES
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The pool of synaptic vesicles that is available for rapid fusion with the presynaptic membrane in response to the arrival of a nerve impulse. These vesicles are docked to the membrane and a proportion of them are biochemically primed for release.
- RESERVE POOL
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A population of synaptic vesicles distal to the active zone that is recruited during periods of high-frequency stimulation.
- ACTIVE ZONE
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A portion of the presynaptic membrane that faces the postsynaptic density across the synaptic cleft. It constitutes the site of synaptic vesicle clustering, docking and transmitter release.
- MINIATURE EXCITATORY POSTSYNAPTIC CURRENTS
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Excitatory synaptic currents observed in the absence of presynaptic action potentials. They are thought to correspond to the discharge of single vesicles.
- PAIRED-PULSE FACILITATION
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When two stimuli are delivered to an axon in quick succession, the response elicited by the second stimulus is larger than that evoked by the first. This phenomenon is termed paired-pulse facilitation, and it is believed to depend on residual calcium that enters the presynaptic terminal.
- POSTSYNAPTIC DENSITY
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An electron-dense thickening underneath the postsynaptic membrane that contains receptors, structural proteins linked to the actin cytoskeleton and signalling elements, such as kinases and phosphatases.
- N-ETHYLMALEIMIDE-SENSITIVE FUSION PROTEIN
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An ATPase that is a key component of the membrane fusion machinery.
- SNARE PROTEINS
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A family of membrane-tethered coiled-coil proteins that regulate exocytotic reactions and target specificity in vesicular fusion processes. SNARE stands for 'soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor'.
- ADAPTOR PROTEIN
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A protein that contributes to cellular function by recruiting other proteins to a complex. Such molecules often contain several protein–protein interaction domains.
- TETRODOTOXIN
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A neurotoxin derived from the Fugu, or puffer fish, that specifically and reversibly blocks voltage-gated sodium channels.
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Vicario-Abejón, C., Owens, D., McKay, R. et al. Role of neurotrophins in central synapse formation and stabilization. Nat Rev Neurosci 3, 965–974 (2002). https://doi.org/10.1038/nrn988
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DOI: https://doi.org/10.1038/nrn988
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