|Spatial and temporal requirements of FMRP function in neurological mechanisms: Defining and employing appropriate intervention windows in Fragile X
By Cheryl Gatto and Kendal Broadie, 5/1/2008
To develop any treatment for Fragile X Syndrome (FraX), it is critical to understand the developmental progression of the disease. It remains poorly understood whether FraX is primarily a ‘developmental disease’, reflecting a transient, age-dependent requirement for the Fragile X Mental Retardation Protein (FMRP) in brain development, a ‘plasticity disease’, reflecting a maintained, constant requirement for FMRP in the mature brain, or some two-phase combination of FMRP requirements giving rise to different FraX symptoms. In other words, do we need FMRP early in life, as a fetus, young child or budding adolescent, to allow normal brain development and to establish a platform for mature brain functions, or is FMRP more important later, and throughout life, to allow brain circuitry and communication to be adjusted as necessary? This knowledge is absolutely vital for the design and implementation of any effective FraX interventions, including therapeutic exploitation of the ‘mGluR (metabotropic glutamate receptor) theory of FraX’. We must know when to treat and why.
In the coming year, we will use our well-established Drosophila FraX disease model to dissect the spatial and temporal requirements for FMRP in behavior regulation, brain structure and synaptic function. FMRP expression will be conditionally driven in the brain using the inducible, transgenic system, called the Gene-Switch (GS) method, in animals otherwise completely lacking FMRP. This approach allows FMRP to be turned on throughout the brain, or within specific targeted brain regions, during defined windows of time. This will enable the definition of the critical periods requiring FMRP, and thus therapeutically targetable signaling events, including mGluR signaling. The findings from these studies will direct the timing of drug trials and subsequent treatments to enhance efficacy and resolution of FraX disease symptoms. If we know when to treat and why, we will be able to improve intervention outcomes.