CBP HAPLOINSUFFICIENCY LEADS TO AGE-RELATED SOCIAL DEFICITS AND HIPPOCAMPAL TRANSCRIPTOMIC AND EPIGENOMIC DYSREGULATION

Rubinstein–Taybi syndrome (RSTS) is a rare congenital disorder characterized by intellectual disability and distinctive facial features, most often caused by heterozygous mutations in the CREBBP gene encoding the lysine acetyltransferase CBP. While over 90% of individuals survive into adulthood, how behavioural phenotypes evolve with aging remains poorly understood. We examined age-related behavioural, neural, and molecular alterations in a heterozygous RSTS mouse model. CBP haploinsufficiency led to impaired social interaction in aged, but not young mice, while social memory deficits were present at both ages. These findings align with clinical reports suggesting age-dependent progression of social deficits (Qu’d et al., 2023). To investigate underlying neural mechanisms, we crossed RSTS mice with the TRAP2 reporter system to label neurons engaged during social memory formation. Aged mice showed reduced neuronal reactivation in the dentate gyrus following social memory re-exposure. We next assessed transcriptomic and epigenomic alterations in hippocampal neurons using nuRNA-seq and Cut&Tag profiling of H3K27ac. Neuronal nuclei were isolated from mouse hippocampi using fluorescence activated nuclei sorting (FANS). CBP deficiency led to increased gene downregulation in aged mice, affecting primarily genes related to synaptic signalling pathways. In addition, we found a global reduction in H3K27 acetylation and identified several thousand regions with reduced H3K27ac, enriched for genes involved in synapse organization, memory, and cognition. Altogether, these findings underscore the interaction between aging and declining socialization in RSTS and highlight the pivotal role of epigenetic dysregulation in its aetiology, supporting the potential use of epigenetic-based therapeutic strategies for phenotypic rescue.