Grant: Project Grant

Fragile-X syndrome (FXS) is a neurodevelopmental disorder that is the most common single-gene cause of autism and inherited intellectual disability. In Canada, it affects 1 in 4,000 boys and 1 in 6,000 girls irrespective of race or ethnic background. FXS results from disrupted expression of the Fragile X Messenger Ribonucleoprotein (FMRP), a RNA binding protein essential for normal brain development. Despite this level of understanding, there is still no cure or specific treatment for FXS. Consequently, any future advances will rely on a better understanding of how the absence of FMRP leads to deficits in the FXS brain. In this grant application, we identify a homeostatic regulatory mechanism that regulates the activity of nerve cells and local blood vessels in a brain region called the cerebellum. We propose that this homeostatic mechanism is found throughout the brain where it maintains the balance between excitatory and inhibitory (E/I) signaling. Importantly, the coupling between neuronal activity and local vessel regulation is lost in a mouse model of FXS but can be rescued with a novel combination therapy of repurposed drugs that boost the deficits in several signaling pathways. The benefit of the proposed project is that it aims to uncover the widespread occurrence of a potentially important defect in FXS that can be corrected by pharmacological treatment.