Characterization and reversibility of cognitive deficits in a mouse model of Tatton-Brown-Rahman syndrome.

• Applicant: Professorin Dr. Ana M. M. Oliveira
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518410300

Tatton-Brown-Rahman syndrome (TBRS) is a recently described rare genetic neurodevelopmental disorder characterized by tall stature, a distinctive facial appearance, and intellectual disability. TBRS is caused by variants in the DNMT3A gene that arise from de novo mutations in the gene. There is no cure for TBRS and treatments are targeted at ameliorating symptoms. Recently, several studies of animal models of neurodevelopmental diseases showed that replacing the dysfunctional gene or targeting gene-related signaling at later developmental stages reversed cognitive deficits in adult mice. It was further demonstrated that the genes associated with these disorders are continuously required for learning and memory throughout life. Hence, indicating that in such cases gene replacement in the mature brain restores at least some disease phenotypes, such as cognitive abilities. Our published and unpublished findings demonstrated a role for the Dnmt3a encoded enzymes, Dnmt3a1 and Dnmt3a2, in the adult hippocampus in memory formation. Therefore, it is conceivable that restoring Dnmt3a function in TBRS mice in adulthood ameliorates cognitive deficits. This hypothesis will be addressed in the current proposal. This will be achieved by taking two main research directions. First, we will uncover the so far unknown alterations in brain and neuronal function in a recently developed mouse model of TBRS. We will characterize brain and morphological features at distinct developmental stages and analyze the performance of Dnmt3aKO/+ mice in a battery of memory tests. Moreover, we will investigate whether neuronal transcriptional responses and activation patterns, relevant for memory formation and retrieval, are affected in these mice and if so, whether they correlate with learning deficits. Second, we will address the reversibility potential of cognitive deficits and associated cellular dysfunctions in the same model. We will focus on the identified molecular, cellular, and behavioral deficits and assess whether gene replacement in adulthood restores these dysfunctions. Overall, this research program is primed to expand our so far very limited understanding of the mechanistic causes of intellectual disability in TBRS. It will provide insight into whether TBRS-like phenotypes are irreversibly determined during development or if at least learning and memory deficits are rescuable upon gene targeting of mature neurons. These findings will pave the way to the development of treatments and interventions.

• DFG Programme: Research Grants
• International Connection: USA
• Co-Investigator: Professorin Dr. Daniela Mauceri
• Cooperation Partner: Professor Harrison Gabel