Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression
- University of North Carolina at Chapel Hill, United States
- Bates College, United States
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.
Article and author information
Author details
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.
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.
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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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
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