Neurotrophin regulation of neural circuit development and function

Key Points

  • Neurotrophins, brain-derived neurotrophic factor (BDNF) in particular, regulate neural circuit development and function. How neural activity controls the expression, processing, secretion and cellular actions of neurotrophins remains to be fully understood.

  • Epigenetic regulation of BDNF transcription, selective localization of different BDNF transcripts and the existence and function of local dendritic BDNF synthesis are areas that require further clarification.

  • In developing circuits, BDNF–tropomyosin-related kinase B (TRKB) signalling regulates neuronal differentiation and growth as well as synapse formation, maturation and refinement, although its previously presumed role in CNS neuronal survival is now seriously challenged by new evidence.

  • In mature neural circuits, BDNF–TRKB signalling modulates synaptic efficacy and synaptic plasticity, such as long-term potentiation (LTP) and long-term depression, via pre- and postsynaptic mechanisms. It may also mediate the formation of stable late-LTP and structural modification of synapses through protein synthesis-dependent mechanisms. The source of synaptically secreted BDNF in vivo remains to be clarified (for example, whether it is a pre- or postsynaptic cell). Whether pro-BDNF is secreted and processed extracellularly at the synapse under physiological conditions remains controversial.

  • Activity-dependent transcytosis and trans-synaptic transfer of neurotrophins are highly relevant to neurotrophin regulation of neural circuits, as these processes provide selective long-range propagation of neurotrophin actions within the neural circuit.

Abstract

Brain-derived neurotrophic factor (BDNF) — a member of a small family of secreted proteins that includes nerve growth factor, neurotrophin 3 and neurotrophin 4 — has emerged as a key regulator of neural circuit development and function. The expression, secretion and actions of BDNF are directly controlled by neural activity, and secreted BDNF is capable of mediating many activity-dependent processes in the mammalian brain, including neuronal differentiation and growth, synapse formation and plasticity, and higher cognitive functions. This Review summarizes some of the recent progress in understanding the cellular and molecular mechanisms underlying neurotrophin regulation of neural circuits. The focus of the article is on BDNF, as this is the most widely expressed and studied neurotrophin in the mammalian brain.

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Figure 1: Local BDNF effects on synaptogenesis.
Figure 2: Modulation of synaptic functions by neurotrophins.
Figure 3: Two models of BDNF actions in LTP of central excitatory synapses.

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Acknowledgements

We thank Y. Barde and B. Lu for extensive comments and suggestions on the early drafts of this manuscript. This work is supported by grants from the US National Institutes of Health (NIH EY014979; NS 036999) and the CHDI (CHDI A3794).

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Correspondence to Mu-ming Poo.

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Glossary

Late-phase long-term potentiation

(L-LTP). Transcription- and translation-dependent synaptic potentiation that persists for more than 3 hours, and is typically induced by multiple trains of high-frequency stimulation spaced at intervals of a few minutes.

Signalling endosomes

Endosomes containing ligand–receptor complexes that remain active, transducing cytoplasmic signals as they are transported within the cell.

Biolostic transfection

A gene transfection technique for injecting DNA-coated subcellular-sized metal particles at high velocity into target cells using an apparatus known as a gene gun.

Ocular dominance plasticity

The relative efficacy of visual inputs from the left and right eye in eliciting responses in the visual cortical neurons can be affected permanently by a brief period of unbalanced visual inputs from the two eyes during postnatal brain development.

Neurotrophic factor hypothesis

Axon terminals from different presynaptic neurons co-innervating the same target cell undergo activity-dependent synaptic competition by competing for a limited supply of a neurotrophic factor secreted by the target cell; terminals that acquire sufficient trophic factor become stabilized, whereas those failing to do so become eliminated. Presumably, axonal activity confers an advantage in the competition.

Early-phase LTP

(E-LTP). A transcription- and translation-independent synaptic potentiation that lasts for 1–3 hours, typically induced by a single train of high-frequency stimulation.

Colchicine

A compound isolated from Colchicum autumnale (autumn crocus) that disrupts microtubule polymerization by binding to tubulin.

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Park, H., Poo, M. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14, 7–23 (2013). https://doi.org/10.1038/nrn3379

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