Mechanosensitive regulation of the GABAergic switch in Jamuar syndrome.

Jamuar Syndrome is a rare and severe childhood brain disorder caused by mutations in a gene called UGDH. This gene helps build important sugar-like molecules—called glycosaminoglycans—that are part of the “scaffolding” surrounding brain cells. This scaffolding, known as the extracellular matrix (ECM), supports neurons, organizes connections between them, and helps regulate brain activity. When UGDH is not functioning properly, the brain’s extracellular environment, hence the ECM, becomes abnormally soft, which can interfere with brain development. We believe that an overly soft ECM may prevent neurons from maturing correctly, especially by disrupting a normal developmental change in how they respond to signals—shifting from being excited to being inhibited. This switch is essential for healthy brain development and function. If neurons fail to mature properly, the brain can become hyperexcitable, leading to epilepsy and developmental delays—hallmark features of Jamuar Syndrome. In this project, we will create a laboratory model of the disease using neurons with and without UGDH activity. These cells will be cultured in 3D gel-like environments with adjustable stiffness, simulating different conditions of brain tissue. This approach will help us understand how the mechanical properties of the ECM influence neuronal development and communication. We will study how well these neurons grow, how they behave electrically, and whether they can adapt properly to changes in network activity. We will also test if boosting the activity of a protein called Piezo1—which helps cells sense mechanical forces—can correct the developmental problems caused by a soft brain environment. In summary, this research aims to uncover a new mechanism linking the biomechanics of the brain’s environment and UGDH mutations to neurological dysfunction. The findings could open new avenues for treating Jamuar Syndrome and other childhood epilepsies associated with abnormal brain development.