Postsynaptic burst reactivation of hippocampal neurons enables associative plasticity of temporally discontiguous inputs

  1. Tanja Fuchsberger
  2. Claudia Clopath
  3. Przemyslaw Jarzebowski
  4. Zuzanna Brzosko
  5. Hongbing Wang
  6. Ole Paulsen  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. Imperial College London, United Kingdom
  3. Michigan State University, United States

Abstract

A fundamental unresolved problem in neuroscience is how the brain associates in memory events that are separated in time. Here we propose that reactivation-induced synaptic plasticity can solve this problem. Previously, we reported that the reinforcement signal dopamine converts hippocampal spike timing-dependent depression into potentiation during continued synaptic activity (Brzosko et al., 2015). Here, we report that postsynaptic bursts in the presence of dopamine produce input-specific LTP in mouse hippocampal synapses 10 minutes after they were primed with coincident pre- and postsynaptic activity (post-before-pre pairing; Δt = -20 ms). This priming activity induces synaptic depression and sets an NMDA receptor-dependent silent eligibility trace which, through the cAMP-PKA cascade, is rapidly converted into protein synthesis-dependent synaptic potentiation, mediated by a signaling pathway distinct from that of conventional LTP. This synaptic learning rule was incorporated into a computational model, and we found that it adds specificity to reinforcement learning by controlling memory allocation and enabling both ‘instructive’ and 'supervised' reinforcement learning. We predicted that this mechanism would make reactivated neurons activate more strongly and carry more spatial information than non-reactivated cells, which was confirmed in freely moving mice performing a reward-based navigation task.

Data availability

Data availabilityExperimental data and code are available at:Code for computational model and code for in vivo analysis (including a link to in vivo data) are available at: https://github.com/przemyslawj/dCA1-reactivations. Data of plasticity experiments and of simulation data from computational model are available at: https://data.mendeley.com/datasets/dx7cdgpcz3/1.

The following data sets were generated

Article and author information

Author details

  1. Tanja Fuchsberger

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Claudia Clopath

    Department of Bioengineering, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4507-8648
  3. Przemyslaw Jarzebowski

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Zuzanna Brzosko

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Hongbing Wang

    Department of Physiology, Michigan State University, East Lansing, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ole Paulsen

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    op210@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2258-5455

Funding

Biotechnology and Biological Sciences Research Council (BB/N019008/1)

  • Tanja Fuchsberger
  • Zuzanna Brzosko
  • Ole Paulsen

Biotechnology and Biological Sciences Research Council (BB/P019560/1)

  • Tanja Fuchsberger
  • Claudia Clopath
  • Ole Paulsen

Biotechnology and Biological Sciences Research Council (Studentship)

  • Przemyslaw Jarzebowski

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

Ethics

Animal experimentation: Experimental procedures and animal use were performed in accordance with UK Home Office regulations of the UK Animals (Scientific Procedures) Act 1986 and Amendment Regulations 2012, following ethical review by the University of Cambridge Animal Welfare and Ethical Review Body (AWERB). All animal procedures were authorized under Personal and Project licences held by the authors.

Reviewing Editor

  1. Marco Capogna, University of Aarhus, Denmark

Version history

  1. Received: June 23, 2022
  2. Preprint posted: June 26, 2022 (view preprint)
  3. Accepted: October 9, 2022
  4. Accepted Manuscript published: October 13, 2022 (version 1)
  5. Version of Record published: October 27, 2022 (version 2)

Copyright

© 2022, Fuchsberger 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

  • 1,853
    Page views
  • 308
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Tanja Fuchsberger
  2. Claudia Clopath
  3. Przemyslaw Jarzebowski
  4. Zuzanna Brzosko
  5. Hongbing Wang
  6. Ole Paulsen
(2022)
Postsynaptic burst reactivation of hippocampal neurons enables associative plasticity of temporally discontiguous inputs
eLife 11:e81071.
https://doi.org/10.7554/eLife.81071

Further reading

    1. Genetics and Genomics
    2. Neuroscience
    Yoshifumi Sonobe, Soojin Lee ... Paschalis Kratsios
    Research Article Updated

    A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A hallmark of ALS/FTD pathology is the presence of dipeptide repeat (DPR) proteins, produced from both sense GGGGCC (poly-GA, poly-GP, poly-GR) and antisense CCCCGG (poly-PR, poly-PG, poly-PA) transcripts. Translation of sense DPRs, such as poly-GA and poly-GR, depends on non-canonical (non-AUG) initiation codons. Here, we provide evidence for canonical AUG-dependent translation of two antisense DPRs, poly-PR and poly-PG. A single AUG is required for synthesis of poly-PR, one of the most toxic DPRs. Unexpectedly, we found redundancy between three AUG codons necessary for poly-PG translation. Further, the eukaryotic translation initiation factor 2D (EIF2D), which was previously implicated in sense DPR synthesis, is not required for AUG-dependent poly-PR or poly-PG translation, suggesting that distinct translation initiation factors control DPR synthesis from sense and antisense transcripts. Our findings on DPR synthesis from the C9ORF72 locus may be broadly applicable to many other nucleotide repeat expansion disorders.

    1. Cell Biology
    2. Neuroscience
    Elisabeth Jongsma, Anita Goyala ... Collin Yvès Ewald
    Research Article Updated

    The amyloid beta (Aβ) plaques found in Alzheimer’s disease (AD) patients’ brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance of extracellular aggregates in vivo, we created a transgenic Caenorhabditis elegans strain that expresses and secretes human Aβ1-42. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease a disintegrin and metalloprotease 2 (ADM-2), an ortholog of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.