A de novo mutation in the DNA methyltransferase 3A gene (Dnmt3a) causes Tatton-Brown-Rahman syndrome (TBRS), a recently described genetic neurodevelopmental disorder that currently has no treatment. Patients display tall stature and intellectual disability. Dnmt3a encodes for the enzymes Dnmt3a1 and Dnmt3a2. These enzymes, according to literature as well as published and unpublished work from our lab, play a crucial role in memory formation in the adult hippocampus. However, how brain and neuronal function is affected in TBRS remains poorly understood. This project aims to bridge this gap of knowledge by using a novel TBRS mouse model.Our preliminary data revealed impairments in hippocampus dependent memory tasks. Additionally, we discovered differences in both gross brain morphology, as well as hippocampal neuronal morphology in these animals. We are currently expanding on these findings by investigating functional connectivity alternations. Additionally, we will assess differences in learning induced transcription and gene expression via RNA sequencing. Finally, engram reactivation rates as well as morphological differences in learning selected neurons will be investigated.Given that recent preclinical gene replacement approaches have yielded positive results for other neurodevelopmental disorders in reversing some of the pathology, in a next step, Dnmt3a will be restored in adult TBRS animals to observe if deficits are ameliorated, and cognitive function is improved. Should the process prove effective, TBRS research will greatly benefit, potentially facilitating the development of more acute treatments moving forward. Furthermore, it would serve to challenge the notion that neurodevelopmental disorder derived cognitive deficits are irreversible in adulthood.