Retinoic acid-gated BDNF synthesis in neuronal dendrites drives presynaptic homeostatic plasticity
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Evaluation Summary:
This manuscript probes the mechanism of postsynaptic retinoic acid (RA) signaling on presynaptic function. BDNF has important roles in synaptic plasticity, but how retrograde BDNF signaling is controlled following synaptic inactivity is unclear. The authors use genetic tools to localize the action of different components of the pathway to pre- or post-synaptic compartments and use biochemical approaches to define a molecular link between retinoic acid and local translation of distinct BDNF transcripts. The findings presented here fill a gap in our knowledge regarding how presynaptic function is adaptively modulated by BDNF by highlighting the role of RA in this process. The experiments have been well-executed and the data provide compelling support for the model proposed by the authors.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)
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Abstract
Homeostatic synaptic plasticity is a non-Hebbian synaptic mechanism that adjusts synaptic strength to maintain network stability while achieving optimal information processing. Among the molecular mediators shown to regulate this form of plasticity, synaptic signaling through retinoic acid (RA) and its receptor, RARα, has been shown to be critically involved in the homeostatic adjustment of synaptic transmission in both hippocampus and sensory cortices. In this study, we explore the molecular mechanism through which postsynaptic RA and RARα regulates presynaptic neurotransmitter release during prolonged synaptic inactivity at mouse glutamatertic synapses. We show that RARα binds to a subset of dendritically sorted brain-derived neurotrophic factor ( Bdnf ) mRNA splice isoforms and represses their translation. The RA-mediated translational de-repression of postsynaptic BDNF results in the retrograde activation of presynaptic tropomyosin receptor kinase B (TrkB) receptors, facilitating presynaptic homeostatic compensation through enhanced presynaptic release. Together, our study illustrates an RA-mediated retrograde synaptic signaling pathway through which postsynaptic protein synthesis during synaptic inactivity drives compensatory changes at the presynaptic site.
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Evaluation Summary:
This manuscript probes the mechanism of postsynaptic retinoic acid (RA) signaling on presynaptic function. BDNF has important roles in synaptic plasticity, but how retrograde BDNF signaling is controlled following synaptic inactivity is unclear. The authors use genetic tools to localize the action of different components of the pathway to pre- or post-synaptic compartments and use biochemical approaches to define a molecular link between retinoic acid and local translation of distinct BDNF transcripts. The findings presented here fill a gap in our knowledge regarding how presynaptic function is adaptively modulated by BDNF by highlighting the role of RA in this process. The experiments have been well-executed and the data provide compelling support for the model proposed by the authors.
(This preprint has been …
Evaluation Summary:
This manuscript probes the mechanism of postsynaptic retinoic acid (RA) signaling on presynaptic function. BDNF has important roles in synaptic plasticity, but how retrograde BDNF signaling is controlled following synaptic inactivity is unclear. The authors use genetic tools to localize the action of different components of the pathway to pre- or post-synaptic compartments and use biochemical approaches to define a molecular link between retinoic acid and local translation of distinct BDNF transcripts. The findings presented here fill a gap in our knowledge regarding how presynaptic function is adaptively modulated by BDNF by highlighting the role of RA in this process. The experiments have been well-executed and the data provide compelling support for the model proposed by the authors.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)
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Reviewer #1 (Public Review):
The authors in this manuscript probe the mechanism of postsynaptic retinoic acid (RA) signaling on presynaptic function. Previous work has established that 1) Inhibition of postsynaptic activity leads to postsynaptic BDNF synthesis and retrograde signaling through presynaptic trk receptors that enhances presynaptic function and 2) Postsynaptic inhibition also leads to postsynaptic RA signaling and presynaptic changes. Here, the authors connect these two observations. First, they show that RA's presynaptic impacts are induced through postsynaptic RA activity. Second, they present compelling evidence that the RA receptor RARalpha binds to dendritically localized isoforms of BDNF mRNA and likely regulates its translation. Finally, the authors demonstrate that RA modulates presynaptic function through …
Reviewer #1 (Public Review):
The authors in this manuscript probe the mechanism of postsynaptic retinoic acid (RA) signaling on presynaptic function. Previous work has established that 1) Inhibition of postsynaptic activity leads to postsynaptic BDNF synthesis and retrograde signaling through presynaptic trk receptors that enhances presynaptic function and 2) Postsynaptic inhibition also leads to postsynaptic RA signaling and presynaptic changes. Here, the authors connect these two observations. First, they show that RA's presynaptic impacts are induced through postsynaptic RA activity. Second, they present compelling evidence that the RA receptor RARalpha binds to dendritically localized isoforms of BDNF mRNA and likely regulates its translation. Finally, the authors demonstrate that RA modulates presynaptic function through postsynaptic BDNF and presynaptic TrkB, consistent with a model in which RA responds to reduced Ca2+ in postsynaptic compartments to increase BDNF synthesis and induce presynaptic plasticity.
Overall these findings fill a gap in our knowledge regarding how presynaptic function is adaptively modulated following postsynaptic inhibition and the connection between RA and BDNF in this process. This provides an important foundation to understand the signaling systems that orchestrate pre- and post-synaptic responses to synaptic inactivity.
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Reviewer #2 (Public Review):
This paper identifies an important molecular pathway that links synaptic inactivity with feedback control of presynaptic neurotransmitter release. Retinoic acid (RA) is known to play a key role in compensatory changes in postsynaptic function following a loss of excitatory synaptic drive, but presynaptic changes accompany this inactivity as well. Here, the authors demonstrate that RA signaling induces local translation of BDNF postsynaptically, which is then released to enhance presynaptic function via presynaptic BDNF-TrkB signaling. Homeostatic control of synapse function is critical for proper information processing in circuits and homeostatic dysfunction has been repeatedly implicated in neurodevelopmental and neuropsychiatric disorders. The findings are thus of high significance and broad interest.
The …
Reviewer #2 (Public Review):
This paper identifies an important molecular pathway that links synaptic inactivity with feedback control of presynaptic neurotransmitter release. Retinoic acid (RA) is known to play a key role in compensatory changes in postsynaptic function following a loss of excitatory synaptic drive, but presynaptic changes accompany this inactivity as well. Here, the authors demonstrate that RA signaling induces local translation of BDNF postsynaptically, which is then released to enhance presynaptic function via presynaptic BDNF-TrkB signaling. Homeostatic control of synapse function is critical for proper information processing in circuits and homeostatic dysfunction has been repeatedly implicated in neurodevelopmental and neuropsychiatric disorders. The findings are thus of high significance and broad interest.
The experiments have been well-executed with appropriate controls. The authors use strong genetic models to define pre- or post-synaptic roles for different components of the RA signaling axis. Overall, the work is rigorous and the findings are well supported by the data shown - this is an outstanding piece of work.
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Reviewer #3 (Public Review):
This work concerns the mechanisms underlying homeostatic synaptic plasticity, a type of negative feedback that helps normalize neuronal activity levels. In the mammalian system, this occurs primarily by post-synaptic changes in neurotransmitter receptor content but under certain conditions pre-synaptic changes in transmitter release also occur.
Following earlier work from this lab using dissociated hippocampal cultures, here they find that older (21+ day old) hippocampal slices culture have both pre- and post-synaptic changes in response to prolonged (36h) blockade of neuronal activity, as measured by an increase in the amplitude and frequency of spontaneous transmitter release from excitatory synapses. This is the standard approach for this type of work. They also verify (as per the earlier work) that both …
Reviewer #3 (Public Review):
This work concerns the mechanisms underlying homeostatic synaptic plasticity, a type of negative feedback that helps normalize neuronal activity levels. In the mammalian system, this occurs primarily by post-synaptic changes in neurotransmitter receptor content but under certain conditions pre-synaptic changes in transmitter release also occur.
Following earlier work from this lab using dissociated hippocampal cultures, here they find that older (21+ day old) hippocampal slices culture have both pre- and post-synaptic changes in response to prolonged (36h) blockade of neuronal activity, as measured by an increase in the amplitude and frequency of spontaneous transmitter release from excitatory synapses. This is the standard approach for this type of work. They also verify (as per the earlier work) that both types of changes depend on retinoic acid (RA) signaling on post-synaptic retinoic acid receptor alpha (RAR). They make nice use of conditional gene deletion to show this.
They also confirm earlier work from the Sutton and Tsien labs that the pre-synaptic homeostatic synaptic plasticity is due to BDNF signaling, with BDNF being produced post-synaptically and signaling retrogradely to TrkB receptors on the pre-synapse. Again, they make good use of conditional gene deletions to demonstrate this clearly.
They then provide new data to link these signals, showing the RAR (a known transcriptional regulator) can directly bind BDNF RNA in synaptoneurosomes and seems to basally suppress translation, as treatment with RA increases BDNF protein production. These data are also convincing. They have done a nice job of linking the previous findings into a complete signaling pathway.
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