Exploring alterations in functional connectivity in Angelman Syndrome

Angelman syndrome (AS) is a neurogenetic disorder primarily caused by loss of function in the maternally inherited UBE3A gene, resulting in a range of symptoms, including severe developmental delays, intellectual disability, motor dysfunction, and unique behavioral features such as frequent laughter. Although genetic and molecular mechanisms of AS are increasingly well understood, there remains a critical need to elucidate how disruptions in neuronal connectivity and excitability at the circuit level contribute to its pathogenesis. In this study, I aimed to address this gap by examining cortical connectivity alterations in an AS mouse model, using wide-field calcium imaging to capture real-time neuronal activity across large cortical areas in awake animals. My results demonstrated that AS model mice exhibited widespread hyperconnectivity by postnatal day 90 (P90) compared to wild-type controls, with statistically significant (p < 0.05) connectivity increases in cortical regions involved in motor and sensory processing. This pattern of hyperconnectivity persisted by P150, highlighting a steady network dysregulation over time. These findings suggest that the absence of UBE3A function drives persistent and enduring alterations of functional connectivity that may underlie key clinical manifestations of AS. These insights may provide a foundation for therapeutic approaches focused on stabilizing network connectivity to mitigate AS symptoms.