Untranslated regions of brain-derived neurotrophic factor mRNA control its translatability and subcellular localization

Lekk, Ingrid; Cabrera-Cabrera, Florencia; Turconi, Giorgio; Tuvikene, Jürgen; Esvald, Eli‐Eelika; Rähni, Annika; Casserly, Laoise; Garton, Daniel R; Andressoo, Jaan‐Olle; Timmusk, Tõnis; Koppel, Indrek

doi:10.1016/j.jbc.2023.102897

Cited by 13 publications

(10 citation statements)

References 87 publications

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“…One additional support to the view that BDNF localizes in post-synaptic terminals has come from our own and other groups studies showing that BDNF mRNA is present in dendrites, but not in axons, and its transport towards the distal dendritic compartment is enhanced in vivo in response to seizures, antidepressants, physical activity (Tongiorgi et al, 2004; Baj et al, 2012) and in vitro, in response to electrical activity, and treatment with NT3 or BDNF itself (Tongiorgi and Baj, 2008; Oe and Yoneda, 2010; Vicario et al, 2015; Mallei et al, 2015; Lekk et al, 2023). As a corollary to these findings on dendritic BDNF mRNA, chimeric BDNF-GFP constructs expressed in cultured neurons show local translation in dendrites in response to electrical activity (Baj et al, 2011; Vaghi et al, 2014 Lekk et al, 2023) and in experimental animals, endogenous BDNF protein and mRNA have an overlapping distribution in the hippocampal laminae containing the dendrites, both in resting conditions and following various types of stimuli (Tongiorgi et al, 2004; Baj et al, 2012). However, it still remains unclear whether the local translation of BDNF occurs in dendrites, or within the spine.…”

Section: Introductionmentioning

confidence: 68%

Chemical-LTP induces confinment of BDNF mRNA under dendritic spines and BDNF protein accumulation inside the spines

Bimbi,

Tongiorgi

2023

Preprint

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The neurotrophin brain-derived neurotrophic factor (BDNF) plays a key role in neuronal development and synaptic plasticity. The discovery that BDNF mRNA can be transported in neuronal dendrites in an activity-dependent manner has suggested that its local translation may support synapse maturation and plasticity. However, a clear demonstration that BDNF mRNA is locally transported and translated at activated synapses in response to long-term potentiation (LTP) is still lacking. Here, we study the dynamics of BDNF mRNA dendritic trafficking following induction of chemical-LTP (cLTP). Dendritic transport of BDNF transcripts was analysed using the MS2 system for mRNA visualization, and chimeric BDNF-GFP constructs were used to monitor protein synthesis in living neurons. We found that within 15' following cLTP induction, most BDNF mRNA granules become stationary and transiently accumulate in the dendritic shaft at the basis of the spines similarly to the control CamkIIalpha; mRNA which increased also inside the spines, at 60' post-cLTP. At 60' but not at 15' from cLTP induction, we observed an increase in BDNF protein levels within the spine. Taken together, these findings suggest that BDNF mRNA trafficking is arrested in the early phase of cLTP, providing a local source of mRNA for translation of BDNF at the basis of the spine followed in the late LTP phase, by translocation of the BDNF protein within the spine head.

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Section: Introductionmentioning

confidence: 68%

Chemical-LTP induces confinment of BDNF mRNA under dendritic spines and BDNF protein accumulation inside the spines

Bimbi,

Tongiorgi

2023

Preprint

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“…While Vaghi et al used 50µM of NE, in the present study treatments were performed at a lower dose (10µM) of the neurotransmitter. It was already shown that each 5'UTR-luciferase BDNF constructs have a different degree of translatability [20,41]. In particular, exon VI showed the lowest rate of basal translatability which may explain why low doses of NE had no effect on translatability of this BDNF variant compared to 50µM.…”

Section: Discussionmentioning

confidence: 97%

“…Thus, the only way to investigate translation of individual BDNF mRNAs is to study arti cial constructs for the different BDNF exons. Indeed, two previous studies investigated the translatability of the different BDNF transcripts under basal conditions and in response to various stimuli using synthetic constructs [20,41].…”

Section: Discussionmentioning

confidence: 99%

Selective Noradrenergic Activation of BDNF Translation by Mirtazapine

Ciraci,

Santoni,

Tongiorgi

2024

Preprint

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Antidepressants are known for their neurotrophic effects, particularly through the regulation of brain-derived neurotrophic factor (BDNF) expression. Mirtazapine, a tetracyclic noradrenergic and specific serotonergic antidepressant (NaSSA) has been observed to upregulate BDNF, though its underlying mechanism remains unclear. In this study, we used the human neuroblastoma SH-SY5Y cell line to investigate whether mirtazapine could enhance BDNF translation by modulating serotonin and/or norepinephrine and their receptors. A 1-hour stimulation with 1 or 10 µM mirtazapine led to downregulation of serotonergic receptors 5HT1A, while increasing ADRA2A and ADRB2 receptors. Mirtazapine at 10 µM upregulated endogenous BDNF after 3h, but not 1h stimulation. To investigate the translation of major BDNF transcripts, we used chimeric BDNF-luciferase constructs with the untranslated 5'UTR exons I, IIc, IV, or VI, and the long version of the 3'UTR. Luciferase assays and Western blotting revealed that mirtazapine selectively enhanced exon-IIc-BDNF-long3'UTR-Luciferase translation. This increase was associated with norepinephrine release and was inhibited by blocking ADRA2A or ADRB2 adrenoceptors for the exon-IIc-BDNF-long3'UTR-Luciferase, and ADR2B for endogenous BDNF. These findings provide a new perspective on the critical role of the noradrenergic system in mediating mirtazapine’s effects on BDNF translation. We propose a novel mechanism of action in which mirtazapine promotes norepinephrine release and noradrenergic responses by upregulating ADRA2A and ADRB2 while downregulating serotonergic receptors.

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“…Additional support for the view that BDNF localises to postsynaptic terminals has come from our own and other group studies showing that BDNF mRNA is present in dendrites, but not in axons, and that its transport to the distal dendritic compartment is increased in vivo, in response to seizures, antidepressants, and physical activity ( Tongiorgi et al, 2004 ; Baj et al, 2012 ), and in vitro , in response to electrical activity and treatment with NT3 or BDNF itself ( Tongiorgi and Baj, 2008 ; Oe and Yoneda, 2010 ; Mallei et al, 2015 ; Vicario et al, 2015 ; Lekk et al, 2023 ). Furthermore, chimeric BDNF-GFP constructs expressed in cultured neurons exhibit local translation in dendrites in response to electrical activity ( Baj et al, 2011 ; Vaghi et al, 2014 ; Lekk et al, 2023 ), and in experimental animals, endogenous BDNF protein and mRNA have an overlapping distribution in the hippocampal laminae containing the dendrites, both in resting conditions and following various types of stimuli ( Tongiorgi et al, 2004 ; Baj et al, 2012 ). Despite these findings, it remains unclear whether BDNF is translated locally in dendrites or within the spine.…”

Section: Introductionmentioning

confidence: 89%

Chemical LTP induces confinement of BDNF mRNA under dendritic spines and BDNF protein accumulation inside the spines

Bimbi,

Tongiorgi

2024

Front. Mol. Neurosci.

View full text Add to dashboard Cite

The neurotrophin brain-derived neurotrophic factor (BDNF) plays a key role in neuronal development and synaptic plasticity. The discovery that BDNF mRNA can be transported in neuronal dendrites in an activity-dependent manner has suggested that its local translation may support synapse maturation and plasticity. However, a clear demonstration that BDNF mRNA is locally transported and translated at activated synapses in response to long-term potentiation (LTP) is still lacking. Here, we study the dynamics of BDNF mRNA dendritic trafficking following the induction of chemical LTP (cLTP). Dendritic transport of BDNF transcripts was analyzed using the MS2 system for mRNA visualization, and chimeric BDNF-GFP constructs were used to monitor protein synthesis in living neurons. We found that within 15 min from cLTP induction, most BDNF mRNA granules become stationary and transiently accumulate in the dendritic shaft at the base of the dendritic spines, while at 30 min they accumulate inside the spine, similar to the control CamkIIα mRNA which also increased inside the spines at 60 min post-cLTP. At 60 min but not at 15 min from cLTP induction, we observed an increase in BDNF protein levels within the spines. Taken together, these findings suggest that BDNF mRNA trafficking is arrested in the early phase of cLTP, providing a local source of mRNA for BDNF translation at the base of the spine followed by translocation of both the BDNF mRNA and protein within the spine head in the late phase of LTP.

show abstract

Untranslated regions of brain-derived neurotrophic factor mRNA control its translatability and subcellular localization

Cited by 13 publications

References 87 publications

Chemical-LTP induces confinment of BDNF mRNA under dendritic spines and BDNF protein accumulation inside the spines

Chemical-LTP induces confinment of BDNF mRNA under dendritic spines and BDNF protein accumulation inside the spines

Selective Noradrenergic Activation of BDNF Translation by Mirtazapine

Chemical LTP induces confinement of BDNF mRNA under dendritic spines and BDNF protein accumulation inside the spines

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