Project 464946

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 mental retardation protein (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 couples the activity of nerve cells with local blood flow in a brain region called the cerebellum. We propose that this homeostatic mechanism is not unique to the cerebellum but found throughout the brain where it maintains the balance between excitatory and inhibitory (E/I) signaling. Importantly, the coupling between neuronal activity and cerebral blood flow is lost in a mouse model of FXS but can be rescued with a small molecule that boosts the deficits in the signaling pathway. 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.