Exercise-induced enhancement of synaptic function triggered by the inverse BAR protein, Mtss1L

Abstract

Exercise is a potent enhancer of learning and memory, yet we know little of the underlying mechanisms that likely include alterations in synaptic efficacy in the hippocampus. To address this issue, we exposed mice to a single episode of voluntary exercise, and permanently marked activated mature hippocampal dentate granule cells using conditional Fos-TRAP mice. Exercise-activated neurons (Fos-TRAPed) showed an input-selective increase in dendritic spines and excitatory postsynaptic currents at 3 days post-exercise, indicative of exercise-induced structural plasticity. Laser-capture microdissection and RNASeq of activated neurons revealed that the most highly induced transcript was Mtss1L, a little-studied I-BAR domain-containing gene, which we hypothesized could be involved in membrane curvature and dendritic spine formation. shRNA-mediated Mtss1L knockdown in vivo prevented the exercise-induced increases in spines and excitatory postsynaptic currents. Our results link short-term effects of exercise to activity-dependent expression of Mtss1L, which we propose as a novel effector of activity-dependent rearrangement of synapses.

Data availability

RNA seq data generated in the manuscript have been deposited at https://www.ncbi.nlm.nih.gov/bioproject/PRJNA481775

The following data sets were generated

Article and author information

Author details

  1. Christina Chatzi

    Vollum Institute, Oregon Health and Science University, Portland, United States
    For correspondence
    chatzi@ohsu.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8922-5617
  2. Gina Zhang

    Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    No competing interests declared.
  3. Wiiliam D Hendricks

    Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    No competing interests declared.
  4. Yang Chen

    Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    No competing interests declared.
  5. Eric Schnell

    Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, United States
    Competing interests
    No competing interests declared.
  6. Richard H Goodman

    Vollum Institute, Oregon Health and Science University, Portland, United States
    For correspondence
    goodmanr@ohsu.edu
    Competing interests
    No competing interests declared.
  7. Gary L Westbrook

    Vollum Institute, Oregon Health and Science University, Portland, United States
    For correspondence
    westbroo@ohsu.edu
    Competing interests
    Gary L Westbrook, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8108-5223

Funding

National Institutes of Health (NS080979)

  • Richard H Goodman
  • Gary L Westbrook

U.S. Department of Defense (W81XWH-18-1-0598)

  • Eric Schnell

U.S. Department of Veterans Affairs (I01-BX002949)

  • Eric Schnell

Lawrence Ellison Foundation

  • Richard H Goodman

National Institutes of Health (F31-NS098597)

  • Wiiliam D Hendricks

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 procedures were performed according to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were in compliance with approved IACUC protocols at Oregon Health & Science University (protocol# TR01-IP00000148). For surgeries, all mice were anesthetized using an isoflurane delivery system (Veterinary Anesthesia Systems Co.) by spontaneous respiration and every effort was made to minimize suffering.All investigators underwent institutional Responsible Conduct & Research training.

Reviewing Editor

  1. John Huguenard, Stanford University School of Medicine, United States

Version history

  1. Received: February 9, 2019
  2. Accepted: June 22, 2019
  3. Accepted Manuscript published: June 24, 2019 (version 1)
  4. Version of Record published: July 4, 2019 (version 2)

Copyright

© 2019, Chatzi 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

  • 10,316
    Page views
  • 872
    Downloads
  • 23
    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. Christina Chatzi
  2. Gina Zhang
  3. Wiiliam D Hendricks
  4. Yang Chen
  5. Eric Schnell
  6. Richard H Goodman
  7. Gary L Westbrook
(2019)
Exercise-induced enhancement of synaptic function triggered by the inverse BAR protein, Mtss1L
eLife 8:e45920.
https://doi.org/10.7554/eLife.45920

Further reading

    1. Neuroscience
    Lucas Y Tian, Timothy L Warren ... Michael S Brainard
    Research Article

    Complex behaviors depend on the coordinated activity of neural ensembles in interconnected brain areas. The behavioral function of such coordination, often measured as co-fluctuations in neural activity across areas, is poorly understood. One hypothesis is that rapidly varying co-fluctuations may be a signature of moment-by-moment task-relevant influences of one area on another. We tested this possibility for error-corrective adaptation of birdsong, a form of motor learning which has been hypothesized to depend on the top-down influence of a higher-order area, LMAN (lateral magnocellular nucleus of the anterior nidopallium), in shaping moment-by-moment output from a primary motor area, RA (robust nucleus of the arcopallium). In paired recordings of LMAN and RA in singing birds, we discovered a neural signature of a top-down influence of LMAN on RA, quantified as an LMAN-leading co-fluctuation in activity between these areas. During learning, this co-fluctuation strengthened in a premotor temporal window linked to the specific movement, sequential context, and acoustic modification associated with learning. Moreover, transient perturbation of LMAN activity specifically within this premotor window caused rapid occlusion of pitch modifications, consistent with LMAN conveying a temporally localized motor-biasing signal. Combined, our results reveal a dynamic top-down influence of LMAN on RA that varies on the rapid timescale of individual movements and is flexibly linked to contexts associated with learning. This finding indicates that inter-area co-fluctuations can be a signature of dynamic top-down influences that support complex behavior and its adaptation.

    1. Genetics and Genomics
    2. Neuroscience
    Muniesh Muthaiyan Shanmugam, Jyotiska Chaudhuri ... Pankaj Kapahi
    Research Article

    The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produce flavorful food ubiquitously, from the baking industry to our everyday lives. However, the Maillard reaction also occurs in all cells, from prokaryotes to eukaryotes, forming Advanced Glycation End-products (AGEs). AGEs are a heterogeneous group of compounds resulting from the irreversible reaction between biomolecules and α-dicarbonyls (α-DCs), including methylglyoxal (MGO), an unavoidable byproduct of anaerobic glycolysis and lipid peroxidation. We previously demonstrated that Caenorhabditis elegans mutants lacking the glod-4 glyoxalase enzyme displayed enhanced accumulation of α-DCs, reduced lifespan, increased neuronal damage, and touch hypersensitivity. Here, we demonstrate that glod-4 mutation increased food intake and identify that MGO-derived hydroimidazolone, MG-H1, is a mediator of the observed increase in food intake. RNAseq analysis in glod-4 knockdown worms identified upregulation of several neurotransmitters and feeding genes. Suppressor screening of the overfeeding phenotype identified the tdc-1-tyramine-tyra-2/ser-2 signaling as an essential pathway mediating AGEs (MG-H1) induced feeding in glod-4 mutants. We also identified the elt-3 GATA transcription factor as an essential upstream regulator for increased feeding upon accumulation of AGEs by partially controlling the expression of tdc-1 gene. Further, the lack of either tdc-1 or tyra-2/ser-2 receptors suppresses the reduced lifespan and rescues neuronal damage observed in glod-4 mutants. Thus, in C. elegans, we identified an elt-3 regulated tyramine-dependent pathway mediating the toxic effects of MG-H1 AGE. Understanding this signaling pathway may help understand hedonistic overfeeding behavior observed due to modern AGEs-rich diets.