With a $183,000 grant from the FRAXA Research Foundation, Dr. Laetitia Davidovic performed a systematic metabolic study of the brain of the FMR1-deficient mice, the mouse model of FXS, using proton nuclear magnetic resonance spectroscopy (1H NMR)-based metabonomics.
Dr. Davidovic has been examining changes in metabolism in various brain regions that are affected in fragile X patients. She has defined a brain-specific metabolic signature of FXS and is testing treatment strategies to restore normal levels of these metabolites.
In close collaboration with Dr. M.-E. Dumas (Imperial College, London, UK), we have performed the systematic metabolic study of the brain of the Fmr1-deficient mice, the mouse model of FXS, using proton nuclear magnetic resonance spectroscopy (1H NMR)-based metabonomics. This type of analysis has never before been applied to the study of FXS, even though it is now gaining considerable interest in the fields of detection and identification of molecular changes associated with the pathophysiology and drug treatment of neurological disorders. 1H NMR-based metabonomics directly provide a rapid and reproducible access to qualitative and quantitative measurement of the small molecules (or metabolites) content of a given sample, including neurotransmitters and neurochemicals.
The metabolic profiling of various brain regions of Fmr1-deficient mice: cortex, cerebellum, striatum and hippocampus reveal a coordinated metabolic signature associated with FXS, involving both neurotransmitters and neurochemicals. The metabolic markers that we have identified unequivocally differentiate FXS mice from control animals, through neurochemical pathways (GABA/glutamate, myo- inositol, acetylcholine) and intermediary pathways (such as bioenergetics, oxidative stress).
The key point of my scientific program is now the development of a metabolomic drug efficacy index for fragile X syndrome in intact tissues and biofluids of its mouse model to monitor treatments efficacy. We are currently analysing biofluids (urine and blood) of FXS mice treated with placebo or MPEP, an mGluR5 antagonist known to revert several of FXS phenotypes to establish this metabolomic drug efficacy index. We will further test molecules targeting the GABAergic, cholinergic, oxidative stress response since these treatments appear relevant to treat FXS. At a later stage, we foresee to perform combinatorial treatments and behavioural tests on FXS animals treated with the most promising molecules to further substantiate their therapeutical potential.