Microglial Tsc2 Loss as a Determinant of Cerebellar Dysfunction in Tuberous Sclerosis Complex: From Mechanism to Early Intervention

Tuberous Sclerosis Complex (TSC) is a genetic condition caused by mutations in either the TSC1 or TSC2 gene, which can alter how the brain develops. Many children with TSC experience epilepsy, learning difficulties, or features of autism, but we still do not fully understand how these problems arise. Most research has focused on neurons, the brain cells that send signals, but very little attention has been given to microglia, the brain’s resident immune cells. Microglia are especially important during early life, when they help refine brain circuits by removing extra or incorrect connections. If this process is altered, circuits may not develop properly. A region of the brain that seems particularly vulnerable in TSC is the cerebellum. Although known for its role in movement, the cerebellum also helps regulate attention, behaviour, and social skills, areas that are often affected in TSC. Because the cerebellum undergoes intense “wiring” and pruning during the first weeks of life, it is a key area to examine for early changes that may influence later development. This project aims to understand whether microglia contribute to early cerebellar changes in TSC. Using a mouse model carrying a TSC2 mutation, we will examine how microglia behave during this critical period and whether they remove too many, too few, or the wrong types of synaptic connections. We will also test whether a short early treatment with low-dose rapamycin, a drug already used in TSC for other symptoms, can help restore normal circuit development. By uncovering whether microglia play a direct role in early brain alterations and whether these changes can be corrected, this work could open the door to earlier and more targeted strategies to protect brain development in children with TSC.