In summary, our study provides the first evidence that TCF4 reinstatement early in development is necessary to maximize therapeutic benefit in PTHS, adding PTHS to the growing list of neurodevelopmental disorders in which mouse models have shown such a critical period which includes Angelman syndrome, Phelan-McDermid syndrome, GRIN1-related disorders, and SYNGAP1-related cognitive impairment (Aceti et al., 2015; Clement et al., 2012; Mei et al., 2016; Mielnik et al., 2021; Silva-Santos et al., 2015). Here, GRIN1 is linked to Pitt-Hopkins syndrome.