Retinoic acid-gated BDNF synthesis in neuronal dendrites drives presynaptic homeostatic plasticity

  1. Shruti Thapliyal
  2. Kristin L Arendt
  3. Anthony G Lau
  4. Lu Chen  Is a corresponding author
  1. Stanford University, United States

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 a RA-mediated retrograde synaptic signaling pathway through which postsynaptic protein synthesis during synaptic inactivity drives compensatory changes at the presynaptic site.

Data availability

All data generated and analyzed in this study are included in the manuscript and supporting files; the source data files contain the numerical data and original images used to generate the figures.

Article and author information

Author details

  1. Shruti Thapliyal

    Department of Neurosurgery, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  2. Kristin L Arendt

    Department of Neurosurgery, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  3. Anthony G Lau

    Department of Neurosurgery, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  4. Lu Chen

    Department of Neurosurgery, Stanford University, Stanford, United States
    For correspondence
    luchen1@stanford.edu
    Competing interests
    Lu Chen, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8097-2699

Funding

National Institute of Mental Health (MH086403)

  • Lu Chen

National Institute of Neurological Disorders and Stroke (NS11566001)

  • Lu Chen

Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD104458)

  • Lu Chen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse studies were performed according to protocols approved by the Stanford University Administrative Panel on Laboratory Animal Care (#29679) . All procedures conformed to NIH Guidelines for the Care and Use of Laboratory Animals and were approved by the Stanford University Administrative Panel.

Copyright

© 2022, Thapliyal et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,322
    views
  • 264
    downloads
  • 10
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

Share this article

https://doi.org/10.7554/eLife.79863

Further reading

    1. Neuroscience
    Barbora Rehak Buckova, Charlotte Fraza ... Jaroslav Hlinka
    Tools and Resources

    Longitudinal neuroimaging studies offer valuable insight into brain development, ageing, and disease progression over time. However, prevailing analytical approaches rooted in our understanding of population variation are primarily tailored for cross-sectional studies. To fully leverage the potential of longitudinal neuroimaging, we need methodologies that account for the complex interplay between population variation and individual dynamics. We extend the normative modelling framework, which evaluates an individual’s position relative to population standards, to assess an individual’s longitudinal change compared to the population’s standard dynamics. Using normative models pre-trained on over 58,000 individuals, we introduce a quantitative metric termed ‘z-diff’ score, which quantifies a temporal change in individuals compared to a population standard. This approach offers advantages in flexibility in dataset size and ease of implementation. We applied this framework to a longitudinal dataset of 98 patients with early-stage schizophrenia who underwent MRI examinations shortly after diagnosis and 1 year later. Compared to cross-sectional analyses, showing global thinning of grey matter at the first visit, our method revealed a significant normalisation of grey matter thickness in the frontal lobe over time—an effect undetected by traditional longitudinal methods. Overall, our framework presents a flexible and effective methodology for analysing longitudinal neuroimaging data, providing insights into the progression of a disease that would otherwise be missed when using more traditional approaches.