Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression

Abstract

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by monoallelic mutation or deletion in the transcription factor 4 (TCF4) gene. Individuals with PTHS typically present in the first year of life with developmental delay and exhibit intellectual disability, lack of speech, and motor incoordination. There are no effective treatments available for PTHS, but the root cause of the disorder, TCF4 haploinsufficiency, suggests that it could be treated by normalizing TCF4 gene expression. Here we performed proof-of-concept viral gene therapy experiments using a conditional Tcf4 mouse model of PTHS and found that postnatally reinstating Tcf4 expression in neurons improved anxiety-like behavior, activity levels, innate behaviors, and memory. Postnatal reinstatement also partially corrected EEG abnormalities, which we characterized here for the first time, and the expression of key TCF4-regulated genes. Our results support a genetic normalization approach as a treatment strategy for PTHS, and possibly other TCF4-linked disorders.

Data availability

Numerical data used to generate all figures are provided in the Figure Source Data files that correspond to figure labels. Single-cell transcriptomic data from the neonatal mouse cortex and the adult mouse nervous system were obtained from GEO accession GSE123335 and from http://mousebrain.org/downloads.html. All code to reproduce the plots is provided at https://github.com/jeremymsimon/Kim_TCF4.

The following previously published data sets were used

Article and author information

Author details

  1. Hyojin Kim

    Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8690-5617
  2. Eric B Gao

    Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Adam Draper

    Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Noah C Berens

    Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7792-0142
  5. Hanna Vihma

    Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xinyuan Zhang

    Department of Chemistry and Biochemistry, Bates College, Lewiston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Alexandra Higashi-Howard

    Department of Chemistry and Biochemistry, Bates College, Lewiston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Kimberly D Ritola

    Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jeremy M Simon

    Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3906-1663
  10. Andrew J Kennedy

    Department of Chemistry and Biochemistry, Bates College, Lewiston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Benjamin Philpot

    Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    For correspondence
    bphilpot@med.unc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2746-9143

Funding

Pitt Hopkins Research Foundation (Ann D. Bornstein Grant)

  • Hyojin Kim
  • Benjamin Philpot

National Institute of Neurological Disorders and Stroke (R01NS114086)

  • Hyojin Kim
  • Benjamin Philpot

Estonian Research Competency Council (PUTJD925)

  • Hanna Vihma

The Orphan Disease Center (MDBR-21-105-Pitt Hopkins)

  • Andrew J Kennedy

The funder (Ben Philpot) had a role in the conceptualization, supervision, data curation, manuscript writing, and the decision to submit the work for publication. The funder (Hyojin Kim) had a role in the investigation, project administration, data curation, analysis, and manuscript writing. Other funders (Hanna Vihma and Andrew J Kennedy) had roles in data acquisition.

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Ethics

Animal experimentation: All research procedures using mice were approved by the Institutional Animal Care and Use Committee at the University of North Carolina at Chapel Hill (IACUC protocol# 20-156.0) and Institutional Animal Care and Use Committee at Bates College (IACUC protocol# 21-05) and conformed to National Institutes of Health guidelines.

Version history

  1. Received: July 18, 2021
  2. Preprint posted: August 4, 2021 (view preprint)
  3. Accepted: April 19, 2022
  4. Accepted Manuscript published: May 10, 2022 (version 1)
  5. Version of Record published: May 10, 2022 (version 2)

Copyright

© 2022, Kim 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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  1. Hyojin Kim
  2. Eric B Gao
  3. Adam Draper
  4. Noah C Berens
  5. Hanna Vihma
  6. Xinyuan Zhang
  7. Alexandra Higashi-Howard
  8. Kimberly D Ritola
  9. Jeremy M Simon
  10. Andrew J Kennedy
  11. Benjamin Philpot
(2022)
Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression
eLife 11:e72290.
https://doi.org/10.7554/eLife.72290

Share this article

https://doi.org/10.7554/eLife.72290

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