UNCOVERING THE SYNAPTIC PHENOTYPE IN SATB2-ASSOCIATED SYNDROME

SATB2‑associated syndrome (SAS) is a multisystem disorder causing moderate‑to‑profound developmental delay and intellectual disability, arising from mutations in the SATB2 gene, which encodes a transcriptional regulator essential for cortical development. Although SATB2’s role in neuronal identity and connectivity is well established, its specific role at the synapse remains poorly defined. The lack of a clear, well-characterized, synaptic phenotype has limited our understanding of the pathology, which is currently only managed with generic neurodevelopmental interventions. To address this gap, we have combined bioinformatic analysis, microscopy, and genetic manipulation in primary neurons to dissect how alterations in SATB2 expression affect synaptic structure and function. Our initial bioinformatic analysis of mouse prefrontal cortex samples revealed a strong correlation between SATB2 expression and genes involved in synaptic organization, including SYT1, GRIA3, NRXN1, GABBR2, and HOMER1, as well as MEF2C, a key regulator of synapse development and plasticity. Building on these findings, we have silenced and overexpressed SATB2 at defined time points of synapse development in primary neuronal cultures to dissect its role in synapse formation independently of developmental connectivity changes. In parallel we have examined the synaptic impact of three SAS‑linked SATB2 point mutations (R239*, R389C, Q524R). Preliminary evidence indicates that SATB2 regulate synaptic function and identify a potentially targetable MEF2C-dependent pathway that may mitigate synaptic deficits. Overall, this work aims to define SATB2‑regulated synaptic pathways underlying SAS‑related cognitive symptoms and establish a mechanistic foundation for future therapeutic development.