Regulation of local translation at the synapse by BDNF
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)
- et al.
Dynamic visualization of local protein synthesis in hippocampal neurons
Neuron
(2001) - et al.
Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons
Cell
(2008) - et al.
A coordinated local translational control point at the synapse involving relief from silencing and MOV10 degradation
Neuron
(2009) - et al.
Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function
Neuron
(2008) - et al.
BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis
Prog. Neurobiol.
(2005) - 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) - et al.
BDNF regulates the expression and traffic of NMDA receptors in cultured hippocampal neurons
Mol. Cell. Neurosci.
(2007) - et al.
Translational control of long-lasting synaptic plasticity and memory
Neuron
(2009) - et al.
Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132
Neuron
(2010) - et al.
The neuroanatomical and neurochemical basis of conditioned fear
Neurosci. Biobehav. Rev.
(1999)
A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP
Neuron
Tropomyosin-related kinase B in the mesolimbic dopamine system: region-specific effects on cocaine reward
Biol. Psychiatry
Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation
Neuron
Translational control by MAPK signaling in long-term synaptic plasticity and memory
Cell
What are the roles of microRNAs at the mammalian synapse?
Neurosci. Lett.
A role for BDNF in the late-phase of hippocampal long-term potentiation
Neuropharmacology
The involvement of brain-derived neurotrophic factor in hippocampal long-term potentiation revealed by gene targeting experiments
J. Physiol. Paris
BDNF-induced synaptic delivery of AMPAR subunits is differentially dependent on NMDA receptors and requires ERK
Neurobiol. Learn. Mem.
A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala
Neuron
BDNF acutely increases tyrosine phosphorylation of the NMDA receptor subunit 2B in cortical and hippocampal postsynaptic densities
Brain Res. Mol. Brain Res.
BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory?
Neurobiol. Learn. Mem.
LTP and LTD: an embarrassment of riches
Neuron
Structural abnormalities of the cerebral cortex in human chromosomal aberrations: a Golgi study
Brain Res.
Brain-derived neurotrophic factor and cocaine addiction
Brain Res.
Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice
Neuron
Mechanism of TrkB-mediated hippocampal long-term potentiation
Neuron
Essential role for TrkB receptors in hippocampus-mediated learning
Neuron
Identification of the major Mr 100,000 substrate for calmodulin-dependent protein kinase III in mammalian cells as elongation factor-2
J. Biol. Chem.
Brain-derived neurotrophic factor regulates AMPA receptor trafficking to post-synaptic densities via IP3R and TRPC calcium signaling
FEBS Lett.
The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP
Cell
Pro-region of neurotrophins determines the processing efficiency
Biochem. Biophys. Res. Commun.
Late expression of brain-derived neurotrophic factor in the amygdala is required for persistence of fear memory
Neurobiol. Learn. Mem.
Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice
Neuron
Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories
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.
Cited by (103)
Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy
2024, Neurobiology of DiseaseThe mechanism of manual muscle testing as proposed by the ventral horn theory
2024, Medical HypothesesEpitranscriptomic regulation of cognitive development and decline
2022, Seminars in Cell and Developmental BiologyDriving effect of BDNF in the spinal dorsal horn on neuropathic pain
2021, Neuroscience Letters