Author(s): Sheryl Anne Vermudez, Vanderbilt University; Aditi Buch, Vanderbilt University; Kelly Weiss, Vanderbilt University; Yuta Moxley, Vanderbilt University; Hemangi Rajpal, Vanderbilt University; Rocco G. Gogliotti, Loyola University Chicago; Colleen M. Niswender, Vanderbilt University //

ABSTRACT: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by loss-of-function (LOF) mutations in the Transcription Factor 4 (TCF4) gene. Interestingly, PTHS closely resembles Rett syndrome (RTT), another neurodevelopmental disorder caused by LOF mutations in a related gene, Methyl-CpG-Binding Protein 2 (MECP2). These two disorders share molecular and behavioral phenotypes, including cognitive and motor dysfunction, in both the preclinical and clinical settings. Based upon this phenotypic/symptom overlap, and the potential clinical application of normalizing MECP2 gene dosage for RTT, we investigated whether such a treatment strategy could be leveraged in a PTHS mouse model. Specifically, we tested the hypothesis that genetic supplementation of MeCP2 would reverse the abnormal phenotypes in PTHS model mice that are Tcf4 haplosufficient, Tcf4+/-.    We interrogated this hypothesis at the preclinical level by introducing a wild-type MECP2 transgene from MeCP2-overexpressing mice (MECP2Tg1/o) to Tcf4+/- mice. Behavioral characterization illustrated that the MECP2 transgene reversed the phenotypes of Tcf4+/- mice, specifically hyperlocomotion, attenuated anxiety and contextual fear learning and memory deficit. Molecular studies suggest that MeCP2 does not impact Tcf4 expression, suggesting a more complex relationship between these two proteins. Subsequent RNA-sequencing studies have identified a subset of genes and pathways in the hippocampus and striatum that are disrupted in Tcf4+/- mice and normalized with the MECP2 transgene. Of note are genes involved in the production of creatinine and in response to cellular stress, which we are currently further evaluating with functional and expression experiments.    Overall, our current preclinical data suggest that treatment increasing MeCP2 dosage could be potentially used for PTHS. Additionally, the transcriptomic studies could highlight other therapeutic targets that could broadly target MECP2¬-related disorders.

Source of Funding: Supported by NIMH pre-doctoral fellowship F31MH119699 (SDV) and grants from the International Rett Syndrome Foundation and the Pitt-Hopkins Research Foundation (CMN).