Dissecting and reverting alterations in synaptic nanoarchitecture in SATB2-associated syndrome

SATB2-associated syndrome (SAS) is a rare disorder that causes significant developmental delays and intellectual disabilities. It is linked to mutations in the SATB2 gene, which helps control how other genes turn on and off during brain development. While researchers know that SATB2 is important for building the brain’s outer layer (the cerebral cortex), much less is known about how it affects the formation and maintenance of synapses, i.e., the tiny connections allowing neurons to communicate. Synaptic problems are likely a major cause of the cognitive challenges seen in people with SAS, yet current treatments are generic and not tailored to the specific needs of this condition. In our preliminary work, we found that SATB2 is closely tied to genes controlling how synapses are built and function, many of which are also linked to other neurodevelopmental conditions like autism. This suggests that SATB2 may act as a master regulator of how brain cells communicate. Our project will now explore how reducing or eliminating SATB2 affects synapse formation and stability in neurons grown in the lab. We will use advanced genetic techniques to manipulate SATB2 levels and super-resolution microscopy to precisely map changes in synapse structure and function. Importantly, we aim to separate effects on synapse development from broader effects on how neurons connect with each other. Our findings suggest that a pathway involving the MEF2C gene might be especially important in this process. By studying and targeting this pathway, we hope to reverse synaptic defects and ultimately improve cognitive functions in the future. This research will provide critical knowledge into how synapses are disrupted in SAS and open the door to developing new, targeted treatments designed specifically for this condition. Ultimately, we believe this research will lead to new treatments that can directly improve communication, learning, and quality of life for people living with SAS.