Regulation of local translation at the synapse by BDNF

doi:10.1016/j.pneurobio.2010.08.004

Progress in Neurobiology

Volume 92, Issue 4, December 2010, Pages 505-516

https://doi.org/10.1016/j.pneurobio.2010.08.004 Get rights and content

Abstract

The neurotrophin brain-derived neurotrophic factor (BDNF) plays a key role in synaptic plasticity, in part due to changes in local protein synthesis. Activation of TrkB (tropomyosin-related kinase B) receptors for BDNF triggers several parallel signaling pathways, including the Ras/ERK, the phosphatidylinositol 3-kinase (PI3-K) and the phospholipase C-γ pathways. Recent studies have elucidated some of the signaling mechanisms that contribute to the regulation of translation activity by BDNF, through modulation of initiation and elongation phases, but the resulting changes in the proteome are not yet fully characterized. The proteins synthesized in response to activation of TrkB receptors by BDNF depend on the mRNAs that are available locally, after delivery and transport along dendrites. Recent studies have shown that BDNF may also play a regulatory role at this level. Furthermore, BDNF regulates transcription activity, thereby affecting the array of mRNAs available to be transported along dendrites. This review highlights the recent advances in the understanding of the diversity of mechanisms that contribute to the regulation of the synaptic proteome by BDNF, which may account for its role in synaptic plasticity.

Research highlights

▶ BDNF is released from different types of neurons in an activity-dependent manner. ▶ BDNF regulates transcription and delivery of specific transcripts to dendrites. ▶ BDNF acts on a subpopulation of RNA-binding proteins. ▶ BDNF regulates local protein synthesis at the synapse. ▶ Local protein synthesis induced by BDNF contributes to long-term synaptic plasticity and memory formation.

Section snippets

Local protein synthesis in dendrites

Although the bulk of mRNAs are translated in the neuronal cell body, local translation of specific mRNAs might be of particular importance for the regulation of protein expression within dendrites and growing axons. The hypothesis that protein translation can take place in post-synaptic compartments came from the pioneer study by Steward and Levy (1982) who observed polyribosomes at the base of several spines in a rosette-like structure, which is the distinctive evidence that they are bound to

BDNF and synaptic plasticity

Changes in synaptic connectivity due to alterations in activity and/or following structural modifications are thought to underlie learning and memory formation. The long-term potentiation (LTP) of hippocampal synapses is the most studied form of synaptic plasticity, and comprises three sequential phases: short-term potentiation, early-LTP (E-LTP) and late LTP (L-LTP). The first two phases are transcription and translation independent, lasting for 1–2 h, and the latter phase depends on

Transcription- and translation-independent synaptic regulation by BDNF

BDNF exerts fast effects on synaptic transmission by post-translational modifications of synaptic proteins, both at the pre- and post-synaptic levels [e.g. (Levine et al., 1995, Lohof et al., 1993)]. Thus, BDNF-induced activation of TrkB receptors increases depolarization-evoked release of glutamate from isolated hippocampal and cerebrocortical nerve terminals (Jovanovic et al., 2000, Pascual et al., 2001, Pereira et al., 2006, Simsek-Duran and Lonart, 2008). Furthermore, the neurotrophin

Regulation of the translation machinery by BDNF

The translation of a given mRNA requires three steps: initiation, elongation and termination. The initiation and elongation steps are considered to be rate-limiting (Herbert and Proud, 2007) and, therefore, subjected to regulation. For initiation to begin the complex eukaryotic initiation factor (eIF) 4F has to be formed in order to recruit both the ribosome and the mRNA molecule. The eIF4F complex is comprised by three subunits with specific functions: eIF4E binds to 5′ capped mRNAs; eIF4A

Dendritic transcripts

One of the mechanisms of regulation of protein synthesis by BDNF at synapses relies on the selective targeting of mRNAs to dendrites (Fig. 2). The most common difficulties in the identification of dendritic transcripts are contamination with somatic material and the low sensitivity of the methods used. Furthermore, the use of different cell types and distinct neuronal development stages may also make difficult the comparison between the results available in the literature. Thus, a microarray

Conclusion

Although it is well established that several activity-induced paradigms can induce local mRNAs translation, additional studies are still required to fully elucidate how different mRNAs are transported and anchored at specific sites along dendrites. Evidences from several studies have shown a great variability in the composition of RNA granules, mainly due to differences between cell type and maturation state. The present challenge is to understand how the specificity of mRNAs/RNPs is achieved

Acknowledgements

The work in the authors laboratory is funded by Fundação para a Ciência e a Tecnologia and FEDER, Portugal (PTDC/SAU-FCF/72283/2006 and POCTI/SAU-NEU/104297/2008).

References (149)

G. Aakalu et al.
Dynamic visualization of local protein synthesis in hippocampal neurons
Neuron
(2001)
J.J. An et al.
Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons
Cell
(2008)
S. Banerjee et al.
A coordinated local translational control point at the synapse involving relief from silencing and MOV10 degradation
Neuron
(2009)
G.J. Bassell et al.
Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function
Neuron
(2008)
C.R. Bramham et al.
BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis
Prog. Neurobiol.
(2005)
M.V. Caldeira et al.
Brain-derived neurotrophic factor regulates the expression and synaptic delivery of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits in hippocampal neurons
J. Biol. Chem.
(2007)
M.V. Caldeira et al.
BDNF regulates the expression and traffic of NMDA receptors in cultured hippocampal neurons
Mol. Cell. Neurosci.
(2007)
M. Costa-Mattioli et al.
Translational control of long-lasting synaptic plasticity and memory
Neuron
(2009)
D. Edbauer et al.
Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132
Neuron
(2010)
M. Fendt et al.
The neuroanatomical and neurochemical basis of conditioned fear
Neurosci. Biobehav. Rev.
(1999)

R. Fonseca et al.

A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP

Neuron

(2006)

D.L. Graham et al.

Tropomyosin-related kinase B in the mesolimbic dopamine system: region-specific effects on cocaine reward

Biol. Psychiatry

(2009)

H. Kang et al.

Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation

Neuron

(1997)

R.J. Kelleher et al.

Translational control by MAPK signaling in long-term synaptic plasticity and memory

Cell

(2004)

A. Konecna et al.

What are the roles of microRNAs at the mammalian synapse?

Neurosci. Lett.

(2009)

M. Korte et al.

A role for BDNF in the late-phase of hippocampal long-term potentiation

Neuropharmacology

(1998)

M. Korte et al.

The involvement of brain-derived neurotrophic factor in hippocampal long-term potentiation revealed by gene targeting experiments

J. Physiol. Paris

(1996)

W. Li et al.

BDNF-induced synaptic delivery of AMPAR subunits is differentially dependent on NMDA receptors and requires ERK

Neurobiol. Learn. Mem.

(2009)

C.H. Lin et al.

A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala

Neuron

(2001)

S.Y. Lin et al.

BDNF acutely increases tyrosine phosphorylation of the NMDA receptor subunit 2B in cortical and hippocampal postsynaptic densities

Brain Res. Mol. Brain Res.

(1998)

Y. Lu et al.

BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory?

Neurobiol. Learn. Mem.

(2008)

R.C. Malenka et al.

LTP and LTD: an embarrassment of riches

Neuron

(2004)

M. Marin-Padilla

Structural abnormalities of the cerebral cortex in human chromosomal aberrations: a Golgi study

Brain Res.

(1972)

J.F. McGinty et al.

Brain-derived neurotrophic factor and cocaine addiction

Brain Res.

(2010)

Y. Meng et al.

Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice

Neuron

(2002)

L. Minichiello et al.

Mechanism of TrkB-mediated hippocampal long-term potentiation

Neuron

(2002)

L. Minichiello et al.

Essential role for TrkB receptors in hippocampus-mediated learning

Neuron

(1999)

A.C. Nairn et al.

Identification of the major Mr 100,000 substrate for calmodulin-dependent protein kinase III in mammalian cells as elongation factor-2

J. Biol. Chem.

(1987)

H. Nakata et al.

Brain-derived neurotrophic factor regulates AMPA receptor trafficking to post-synaptic densities via IP3R and TRPC calcium signaling

FEBS Lett.

(2007)

I. Napoli et al.

The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP

Cell

(2008)

H. Nomoto et al.

Pro-region of neurotrophins determines the processing efficiency

Biochem. Biophys. Res. Commun.

(2007)

L.C. Ou et al.

Late expression of brain-derived neurotrophic factor in the amygdala is required for persistence of fear memory

Neurobiol. Learn. Mem.

(2010)

S.L. Patterson et al.

Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice

Neuron

(1996)

N. Plath et al.

Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories

Neuron

(2006)

G. Aicardi et al.

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

Proc. Natl. Acad. Sci. USA

(2004)

J. Alder et al.

Early presynaptic and late postsynaptic components contribute independently to brain-derived neurotrophic factor-induced synaptic plasticity

J. Neurosci.

(2005)

C. Bagni et al.

From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome

Nat. Rev. Neurosci.

(2005)

C. Bakker et al.

Fmr1 knockout mice: a model to study fragile X mental retardation. The Dutch-Belgian Fragile X Consortium

Cell

(1994)

C.R. Bramham et al.

The Arc of synaptic memory

Exp. Brain Res.

(2010)

K.E. Burgin et al.

In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain

J. Neurosci.

(1990)

A.L. Carvalho et al.

Role of the brain-derived neurotrophic factor at glutamatergic synapses

Br. J. Pharmacol.

(2008)

G. Chen et al.

Relative contribution of endogenous neurotrophins in hippocampal long-term potentiation

J. Neurosci.

(1999)

N. Cougot et al.

Dendrites of mammalian neurons contain specialized P-body-like structures that respond to neuronal activation

J. Neurosci.

(2008)

K.K. Cowansage et al.

Brain-derived neurotrophic factor: a dynamic gatekeeper of neural plasticity

Curr. Mol. Pharmacol.

(2010)

M. Davis

Neurobiology of fear responses: the role of the amygdala

J. Neuropsychiatry Clin. Neurosci.

(1997)

C. Dong et al.

Proteasome inhibition enhances the induction and impairs the maintenance of late-phase long-term potentiation

Learn. Mem.

(2008)

J. Eberwine et al.

Analysis of subcellularly localized mRNAs using in situ hybridization, mRNA amplification, and expression profiling

Neurochem. Res.

(2002)

A. Figurov et al.

Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus

Nature

(1996)

R. Fiore et al.

Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels

EMBO J.

(2009)

A. Gartner et al.

Hippocampal long-term potentiation is supported by presynaptic and postsynaptic tyrosine receptor kinase B-mediated phospholipase Cgamma signaling

J. Neurosci.

(2006)

Cited by (103)

Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy
2024, Neurobiology of Disease
Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest protein family genetically linked to CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRS^E196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for several mutant glycyl-tRNA synthetases linked to CMT type 2D (CMT2D). We then performed temporal neuromuscular assessments of Yars^E196K mice modelling DI-CMT. We determined that Yars^E196K homozygotes display a selective, age-dependent impairment in in vivo axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This impairment is replicated by injection of recombinant TyrRS^E196K, but not TyrRS^WT, into muscles of wild-type mice. Augmenting BDNF in DI-CMTC muscles, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a non-cell autonomous pathomechanism common to ARS-related neuropathies, and highlights the potential of boosting BDNF levels in muscles as a therapeutic strategy.
The mechanism of manual muscle testing as proposed by the ventral horn theory
2024, Medical Hypotheses
It is hypothesized that the central integrative state (CIS) of the spinal cord’s ventral horn depends upon myriad inputs from primary afferentation secondary to gravitational perturbation of joint mechanoreceptors. Further, the current perspective of manual muscle testing (MMT) and diagnostic muscle testing (DMT) research—each being universially accepted by the medical community—tends to focus exclusively on the conditional state of the muscle and/or the α-motoneuron affecting that muscle. Diagnostic muscle testing, however, is mainly an assessment tool for functional disorders. Moreover, since the human brain is receptor dependent, the entirety of the human neurological environment extends from the primary peripheral receptor and its subsequent action potential to the dosral root ganglion, dorsal horn of the spinal cord, and rostral neuroaxial centers like the cerebellum, midbrain, thalamus, and cortex—and ultimately to the effector, including all components in between. The human nervous system concerns itself with whole body reactions, not individual muscles. The premise here is that the highest primary afferentation is secondary to mechanoreceptor deformation after gravitational perturbation. The goal of treatment is to facilitate the patient’s highest level of human performance by recognizing and treating discrete pathology while avoiding an iatrogenic effect. Merely focusing on the α-motoneuron and/or its influence on the effector generates a myopic understanding that loses appreciation of efferent autonomic drive and structural performance. An individual muscle focus does not recognize the complexity of homologous involvement.
Transcranial direct current stimulation attenuates chronic pain in knee osteoarthritis by modulating BDNF/TrkB signaling in the descending pain modulation system
2023, Neuroscience Letters
Knee osteoarthritis (KOA) is the most common cause of chronic pain, but its pain mechanisms are complex and may be closely related to the descending pain modulation system. Transcranial direct current stimulation (tDCS) is used for relieving pain, but its analgesic mechanisms are still being explored. The purpose of this study was to investigate the role of BDNF/TrkB signaling in chronic pain in KOA and to investigate whether this signaling is related to the analgesic effect of tDCS. Rats were injected with monosodium iodoacetate (MIA) into the left knee joint to establish a chronic pain model and then received 20 min of tDCS for 8 days. Rats were respectively administered the TrkB inhibitor ANA-12 after MIA modeling and exogenous BDNF after tDCS treatment. Behaviors testing was assessed by hot plate and von Frey hairs using the up-down method. In addition, the expression levels of BDNF and TrkB on the periaqueductal gray (PAG)-the rostral ventromedial medulla (RVM)-the spinal dorsal horn (SDH) axis were detected by Western blot and Immunohistochemistry staining. Behavioral results show that tDCS treatment and ANA-12 injection reversed MIA-induced allodynia while reducing BDNF and TrkB expression levels. Furthermore, injection of exogenous BDNF reversed the therapeutic effect of tDCS on pain. These results indicate that upregulation of the BDNF/TrkB signaling in the descending pain modulation system may play an important role in KOA-induced chronic pain in rats, and tDCS may reduce KOA-induced chronic pain by inhibiting the BDNF/TrkB signaling in the descending pain modulation system.
Neuronal RNA granules are ribosome complexes stalled at the pre-translocation state: Neuronal RNA granules as ribosome containing complexes
2022, Journal of Molecular Biology
The polarized cell morphology of neurons dictates many neuronal processes, including the axodendridic transport of specific mRNAs and subsequent translation. mRNAs together with ribosomes and RNA-binding proteins form RNA granules that are targeted to axodendrites for localized translation in neurons. It has been established that localized protein synthesis in neurons is essential for long-term memory formation, synaptic plasticity, and neurodegeneration. We have used proteomics and electron microscopy to characterize neuronal RNA granules (nRNAg) isolated from rat brain tissues or human neuroblastoma. We show that ribosome-containing RNA granules are morula-like structures when visualized by electron microscopy. Crosslinking-coupled mass-spectrometry identified a potential G3BP2 binding site on the ribosome near the eIF3d-binding site on the 40S ribosomal subunit. We used cryo-EM to resolve the structure of the ribosome-component of nRNAg. The cryo-EM reveals that predominant particles in nRNAg are 80S ribosomes, resembling the pre-translocation state where tRNA’s are in the hybrid A/P and P/E site. We also describe a new kind of principal motion of the ribosome, which we call the rocking motion.
Epitranscriptomic regulation of cognitive development and decline
2022, Seminars in Cell and Developmental Biology
Functional genomics and systems biology have opened new doors to previously inaccessible genomic information and holistic approaches to study complex networks of genes and proteins in the central nervous system. The advances are revolutionizing our understanding of the genetic underpinning of cognitive development and decline by facilitating identifications of novel molecular regulators and physiological pathways underlying brain function, and by associating polymorphism and mutations to cognitive dysfunction and neurological diseases. However, our current understanding of these complex gene regulatory mechanisms has yet lacked sufficient mechanistic resolution for further translational breakthroughs. Here we review recent findings from the burgeoning field of epitranscriptomics in association of cognitive functions with a special focus on the epitranscritomic regulation in subcellular locations such as chromosome, synapse, and mitochondria. Although there are important gaps in knowledge, current evidence is suggesting that this layer of RNA regulation may be of particular interest for the spatiotemporally coordinated regulation of gene networks in developing and maintaining brain function that underlie cognitive changes.
Driving effect of BDNF in the spinal dorsal horn on neuropathic pain
2021, Neuroscience Letters
Neuropathic pain (NP) is caused by direct or indirect damage to the nervous system and is a common symptom of many diseases. The mechanisms underlying the onset and persistence of NP are unclear. Therefore, research concerning these mechanisms has become an important focus in the medical field. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic factor family of signaling molecules. BDNF is an important regulator of neuronal development, synaptic transmission, and cellular and synaptic plasticity, which are essential for nerve maintenance and repair. However, BDNF is upregulated in the spinal dorsal horn and can promote NP by activating glial cells, reducing inhibitory functions and enhancing excitement after nociceptive stimulation. This review considers the relationship between NP and BDNF signaling in the spinal dorsal horn and discusses potentially related pathological mechanisms.

View all citing articles on Scopus

View full text

Regulation of local translation at the synapse by BDNF

Abstract

Research highlights

Section snippets

Local protein synthesis in dendrites

BDNF and synaptic plasticity

Transcription- and translation-independent synaptic regulation by BDNF

Regulation of the translation machinery by BDNF

Dendritic transcripts

Conclusion

Acknowledgements

Neuron

Cell

Neuron

Neuron

Prog. Neurobiol.

J. Biol. Chem.

Mol. Cell. Neurosci.

Neuron

Neuron

Neurosci. Biobehav. Rev.

Neuron

Biol. Psychiatry

Neuron

Cell

Neurosci. Lett.

Neuropharmacology

J. Physiol. Paris

Neurobiol. Learn. Mem.

Neuron

Brain Res. Mol. Brain Res.

Neurobiol. Learn. Mem.

Neuron

Brain Res.

Brain Res.

Neuron

Neuron

Neuron

J. Biol. Chem.

FEBS Lett.

Cell

Biochem. Biophys. Res. Commun.

Neurobiol. Learn. Mem.

Neuron

Neuron

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

Proc. Natl. Acad. Sci. USA

Early presynaptic and late postsynaptic components contribute independently to brain-derived neurotrophic factor-induced synaptic plasticity

J. Neurosci.

From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome

Nat. Rev. Neurosci.

Fmr1 knockout mice: a model to study fragile X mental retardation. The Dutch-Belgian Fragile X Consortium

Cell

The Arc of synaptic memory

Exp. Brain Res.

In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain

J. Neurosci.

Role of the brain-derived neurotrophic factor at glutamatergic synapses

Br. J. Pharmacol.

Relative contribution of endogenous neurotrophins in hippocampal long-term potentiation

J. Neurosci.

Dendrites of mammalian neurons contain specialized P-body-like structures that respond to neuronal activation

J. Neurosci.

Brain-derived neurotrophic factor: a dynamic gatekeeper of neural plasticity

Curr. Mol. Pharmacol.

Neurobiology of fear responses: the role of the amygdala

J. Neuropsychiatry Clin. Neurosci.

Proteasome inhibition enhances the induction and impairs the maintenance of late-phase long-term potentiation

Learn. Mem.

Analysis of subcellularly localized mRNAs using in situ hybridization, mRNA amplification, and expression profiling

Neurochem. Res.

Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus

Nature

Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels

EMBO J.

Hippocampal long-term potentiation is supported by presynaptic and postsynaptic tyrosine receptor kinase B-mediated phospholipase Cgamma signaling

J. Neurosci.