1. Neuroscience
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Experience-dependent weakening of callosal synaptic connections in the absence of postsynaptic FMRP

  1. Zhe Zhang
  2. Jay R Gibson  Is a corresponding author
  3. Kimberly M Huber  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. The University of Texas Southwestern Medical Center, United States
Research Article
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Cite this article as: eLife 2021;10:e71555 doi: 10.7554/eLife.71555

Abstract

Reduced structural and functional interhemispheric connectivity correlates with the severity of Autism Spectrum Disorder (ASD) behaviors in humans. Little is known of how ASD-risk genes regulate callosal connectivity. Here we show that Fmr1, whose loss-of-function leads to Fragile X Syndrome (FXS), cell autonomously promotes maturation of callosal excitatory synapses between somatosensory barrel cortices in mice. Postnatal, cell-autonomous deletion of Fmr1 in postsynaptic Layer (L) 2/3 or L5 neurons results in a selective weakening of AMPA receptor- (R), but not NMDA receptor-, mediated callosal synaptic function, indicative of immature synapses. Sensory deprivation by contralateral whisker trimming normalizes callosal input strength, suggesting that experience-driven activity of postsynaptic Fmr1 KO L2/3 neurons weakens callosal synapses. In contrast to callosal inputs, synapses originating from local L4 and L2/3 circuits are normal, revealing an input-specific role for postsynaptic Fmr1 in regulation of synaptic connectivity within local and callosal neocortical circuits. These results suggest direct cell autonomous and postnatal roles for FMRP in development of specific cortical circuits and suggest a synaptic basis for long-range functional underconnectivity observed in FXS patients.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures and figure supplements.

Article and author information

Author details

  1. Zhe Zhang

    University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2859-3859
  2. Jay R Gibson

    Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Jay.Gibson@UTSouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
  3. Kimberly M Huber

    Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    kimberly.huber@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7479-0661

Funding

National Institutes of Health (R01 HD052731)

  • Jay R Gibson
  • Kimberly M Huber

National Institutes of Health (U54HD082008)

  • Jay R Gibson
  • Kimberly M Huber

National Institutes of Health (U54HD104461)

  • Jay R Gibson
  • Kimberly M Huber

National Institutes of Health (R03MH104366)

  • Jay R Gibson

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (2017-101986) of the University of Texas Southwestern Medical Center.

Reviewing Editor

  1. Sacha B Nelson, Brandeis University, United States

Publication history

  1. Received: June 23, 2021
  2. Accepted: October 6, 2021
  3. Accepted Manuscript published: October 7, 2021 (version 1)

Copyright

© 2021, Zhang 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.

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