Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
Eric B Gao
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
Xinyuan Zhang
Department of Chemistry and Biochemistry, Bates College, Lewiston, United States
Alexandra Higashi-Howard
Department of Chemistry and Biochemistry, Bates College, Lewiston, United States
Kimberly D Ritola
HHMI Janelia Research Campus, Ashburn, United States
Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States; Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hil, Chapel Hill, United States
Andrew J Kennedy
Department of Chemistry and Biochemistry, Bates College, Lewiston, United States
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States; Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hil, Chapel Hill, United States
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.
