Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression
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Evaluation Summary:
This manuscript by Kim et al. validates the previously generated Tcf4 LGSL mouse model (developed by the authors' group; Kim et al. 2020) for Pitt-Hopkins syndrome (PHS) by normalizing the Tcf4 expression level. They found that reinstating Tcf4 expression improves a subset of behavioral abnormalities, including anxiety-like behavior, activity level, innate behaviors and memory. Moreover, neonatal ICV injection of Cre mediating restoration of gene expression also improved the behavioral abnormalities and altered LFP spectra, and partially recovered the expression level of downstream target genes for Tcf4. This provides a proof-of-concept for therapeutic interventions against PHS. The writing and data quality are excellent, and clear limitations of current study are well described. However, there are some areas for further improvement.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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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.
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Evaluation Summary:
This manuscript by Kim et al. validates the previously generated Tcf4 LGSL mouse model (developed by the authors' group; Kim et al. 2020) for Pitt-Hopkins syndrome (PHS) by normalizing the Tcf4 expression level. They found that reinstating Tcf4 expression improves a subset of behavioral abnormalities, including anxiety-like behavior, activity level, innate behaviors and memory. Moreover, neonatal ICV injection of Cre mediating restoration of gene expression also improved the behavioral abnormalities and altered LFP spectra, and partially recovered the expression level of downstream target genes for Tcf4. This provides a proof-of-concept for therapeutic interventions against PHS. The writing and data quality are excellent, and clear limitations of current study are well described. However, there are some areas for …
Evaluation Summary:
This manuscript by Kim et al. validates the previously generated Tcf4 LGSL mouse model (developed by the authors' group; Kim et al. 2020) for Pitt-Hopkins syndrome (PHS) by normalizing the Tcf4 expression level. They found that reinstating Tcf4 expression improves a subset of behavioral abnormalities, including anxiety-like behavior, activity level, innate behaviors and memory. Moreover, neonatal ICV injection of Cre mediating restoration of gene expression also improved the behavioral abnormalities and altered LFP spectra, and partially recovered the expression level of downstream target genes for Tcf4. This provides a proof-of-concept for therapeutic interventions against PHS. The writing and data quality are excellent, and clear limitations of current study are well described. However, there are some areas for further improvement.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
This manuscript aimed to develop the animal models for Pitt-Hopkins syndrome (PHS) by showing a number of behavioral data and electrophysiological recordings. The major strength is employing sophisticated transgenic Tcf4 mouse model and high-quality of data. The limitation is the marginal rescue effects by Tcf4 reinstatement and murky interpretation of some results. Given the widespread expression of Tcf4 in central nervous system, extreme caution is required for considering the current mouse model for PHS pathogenesis.
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Reviewer #2 (Public Review):
Mutations in the TCF4 gene leads to Pitt Hopkins Syndrome, a neurodevelopmental disorder. This study demonstrates that restoring the typical TCF4 gene in most, but not all, cells of the brains in a mouse model of TCF4 gene deletion can have a beneficial effect on the behavioral symptoms of Pitt Hopkins Syndrome if given very early in brain development. Much more work is needed to determine if such an approach is actually feasible in patients because current gene therapies are not able to be performed in the same manner in humans as was done in this mouse study. Additional future studies will be needed to determine if such a treatment approach in mouse models will be useful later in brain development. Additional controls for effects of the virus used for their mouse gene therapy would have been useful.
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