BDNF mechanisms in late LTP formation: A synthesis and breakdown

doi:10.1016/j.neuropharm.2013.06.024

Neuropharmacology

Volume 76, Part C, January 2014, Pages 664-676

https://doi.org/10.1016/j.neuropharm.2013.06.024 Get rights and content

Highlights

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BDNF-TrkB regulates late LTP through diverse mechanisms.
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TrkB-coupled translational control and actin cytoskeletal regulation.
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BDNF rescue of late LTP.
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Brain region-specific mechanisms.
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Pathway cross-talk and signal bias.

Abstract

Unraveling the molecular mechanisms governing long-term synaptic plasticity is a key to understanding how the brain stores information in neural circuits and adapts to a changing environment. Brain-derived neurotrophic factor (BDNF) has emerged as a regulator of stable, late phase long-term potentiation (L-LTP) at excitatory glutamatergic synapses in the adult brain. However, the mechanisms by which BDNF triggers L-LTP are controversial. Here, we distill and discuss the latest advances along three main lines: 1) TrkB receptor-coupled translational control underlying dendritic protein synthesis and L-LTP, 2) Mechanisms for BDNF-induced rescue of L-LTP when protein synthesis is blocked, and 3) BDNF-TrkB regulation of actin cytoskeletal dynamics in dendritic spines. Finally, we explore the inter-relationships between BDNF-regulated mechanisms, how these mechanisms contribute to different forms of L-LTP in the hippocampus and dentate gyrus, and outline outstanding issues for future research.

This article is part of the Special Issue entitled ‘BDNF Regulation of Synaptic Structure, Function, and Plasticity’.

Introduction

The compartmentalization of electrical and biochemical signals in dendritic spines makes glutamatergic synapses a natural locus for encoding information in neural networks. Hence, activity-dependent forms of synaptic plasticity, such as long-term potentiation (LTP), long-term depression (LTD), and homeostatic plasticity (scaling), are of immense interest for elucidating the molecular mechanisms of memory formation, storage, and forgetting. Stable, late phase LTP (L-LTP) is associated with enlargement and remodeling of the postsynaptic density (PSD), enlargement of pre-existing dendritic spines, as well as de novo synapse formation (Lisman and Raghavachari, 2006, Bourne and Harris, 2008). Such large-scale growth and remodeling is thought to require de novo synthesis of synaptic proteins, along with protein trafficking and degradation.

The secretory peptide, brain-derived neurotrophic factor (BDNF), plays a critical role in stimulating the formation of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms by which BDNF promotes L-LTP have not been established for any specific brain region. Glutamatergic synapses are capable of expressing mechanistically distinct forms of LTP, and glutamatergic synapses differ in morphology, physiology, and molecular composition between brain regions and between synapses on the same neuron. With a focus on how BDNF signaling controls L-LTP, we distill and discuss the latest advances along three main lines: 1) tropomyosin-like kinase B (TrkB) receptor-coupled translational control underlying local protein synthesis and L-LTP, 2) mechanisms for BDNF-induced rescue of L-LTP when protein synthesis is blocked, and 3) BDNF-TrkB regulation of dendritic spine cytoskeletal dynamics. Finally, we seek to understand the functional relationships between these mechanisms and outline the major outstanding issues.

Section snippets

BDNF as a trigger for protein synthesis-dependent late LTP

Classically, LTP maintenance is split into early and late phases in which only the late, stable phase is blocked by protein synthesis inhibitors (PSIs) (Krug et al., 1984, Stanton and Sarvey, 1984, Frey et al., 1988, Otani et al., 1989, Matthies et al., 1990, Abraham and Williams, 2008, Mayford et al., 2012). As underscored by Routtenberg (2008), the use of PSIs to define the physiological role of protein synthesis has significant caveats. By rapidly inhibiting almost all cellular protein

BDNF and protein synthesis-independent LTP stabilization

TBS-LTP in region CA1 of hippocampal slices is considered to be a local form of LTP requiring BDNF signaling and dendritic translation, but not somatic transcription (Huang and Kandel, 2005, Sajikumar and Korte, 2011). Several studies demonstrate that inhibition of late TBS-LTP by PSIs is overcome by perfusing slice with BDNF (Pang et al., 2004, Santi et al., 2006). In this paradigm, stable TBS-LTP is rescued when BDNF is applied no later than 15 min post-TBS. Santi et al. (2006) further

BDNF regulation of actin cytoskeletal dynamics

Regulation of actin cytoskeletal dynamics in dendritic spines is required for LTP formation and associated enlargement of dendritic spines (Bourne et al., 2007, Bramham, 2008, Murakoshi and Yasuda, 2012). Much has been learned about mechanisms of actin regulation in spines and the diverse functions of spine F-actin and actin-based motor proteins in receptor and membrane trafficking, organelle movement, and remodeling of the PSD (Frost et al., 2010, Penzes and Rafalovich, 2012, Kneussel and

Multiple BDNF mechanisms, brain region differences

Three general conclusions can be reached. First, BDNF-TrkB can promote L-LTP induction through multiple protein synthesis-dependent mechanisms. Second, these mechanisms differ between the CA1 region and dentate gyrus, and probably as a function of the type of LTP induced (TBS or HFS). Third, BDNF synthesized in response to TBS in the CA1 region promotes stable L-LTP through a protein synthesis-independent mechanism. The properties of different forms of L-LTP and BDNF rescue are summarized in

Acknowledgments

Supported by The Research Council of Norway.

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Invited reviewBDNF mechanisms in late LTP formation: A synthesis and breakdown

Highlights

Abstract

Introduction

Section snippets

BDNF as a trigger for protein synthesis-dependent late LTP

BDNF and protein synthesis-independent LTP stabilization

BDNF regulation of actin cytoskeletal dynamics

Multiple BDNF mechanisms, brain region differences

Acknowledgments

Neuron

Neuroscience Research

Neurobiology of Learning and Memory

Cell

Neuron

Current Opinion in Neurobiology

Neuron

Current Opinion in Neurobiology

Progress in Neurobiology

Neuron

Journal of Biological Chemistry

Trends in Neurosciences

Brain Research

Neuron

Neuropharmacology

Neuroscience Letters

Brain Research

Current Opinion in Neurobiology

The Journal of Biological Chemistry

Neurobiology of Aging

Cell

Neuroscience Letters

Journal of Biological Chemistry

Cell

Neuron

Journal of Biological Chemistry

Neuron

Cell

Neuropharmacology

Trends in Neurosciences

Brain Research Bulletin

Induction of long-term potentiation and depression is reflected by corresponding changes in secretion of endogenous brain-derived neurotrophic factor

Proceedings of the National Academy of Sciences of the United States of America

Selective modulation of some forms of schaffer collateral-CA1 synaptic plasticity in mice with a disruption of the CPEB-1 gene

Learning & Memory

Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity

Learning & Memory (Cold Spring Harbor, N.Y.)

Spatial segregation of BDNF transcripts enables BDNF to differentially shape distinct dendritic compartments

Proceedings of the National Academy of Sciences

The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus

Journal of Neuroscience

BDNF and memory processing

Neuropharmacology

Biology of the p21-activated kinases

Annual Review of Biochemistry

Balancing structure and function at hippocampal dendritic spines

Annual Review of Neuroscience

Polyribosomes are increased in spines of CA1 dendrites 2 h After the induction of LTP in mature rat hippocampal slices

Hippocampus

A role for dendritic protein synthesis in hippocampal late LTP

European Journal of Neuroscience

The Arc of synaptic memory

Experimental Brain Research

Dendritic mRNA: transport, translation and function

Nature Reviews Neuroscience

Calpain-2-Mediated PTEN degradation contributes to BDNF-induced stimulation of dendritic protein synthesis

Journal of Neuroscience

Fluorescent and photo-oxidizing TimeSTAMP tags track protein fates in light and electron microscopy

Nature Neuroscience

The Mnks: MAP kinase-interacting kinases (MAP kinase signal-integrating kinases)

Frontiers in Bioscience

Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1

Proceedings of the National Academy of Sciences of the United States of America

Amnesia produced by altered release of neurotransmitters after intraamygdala injections of a protein synthesis inhibitor

Proceedings of the National Academy of Sciences of the United States of America

Neurotrophin release by neurotrophins: implications for activity-dependent neuronal plasticity

Proceedings of the National Academy of Sciences of the United States of America

Impairment of TrkB-PSD-95 signaling in Angelman syndrome

PLoS Biology

Invited review
BDNF mechanisms in late LTP formation: A synthesis and breakdown