Laetitia Davidovic, PhD, Principal Investigator

FRAXA Awards:

by Laetitia Davidovic, 6/9/2011

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.

by Laetitia Davidovic, 5/28/2009

The research program I am developing is aimed at understanding the physiopathology of fragile X syndrome via several complementary approaches. One approach involves 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, in close collaboration with Dr. M.-E. Dumas (Imperial College, London, UK). 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.

Thanks to the support of FRAXA, we have now completed the 1H NMR analyses and metabolic profiling of various brain regions of Fmr1-deficient mice: cortex, cerebellum, striatum and hippocampus. All brain regions show 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 next phase of the project involves testing the ability of several novel molecules to reverse the Fmr1-KO mouse brain metabolic phenotype. First, we will assess to which extent treatment with the mGluR5 antagonist MPEP efficiently restores the altered metabolic profile in Fmr1-KO mice, as it improves various phenotypic traits in the mouse model of FXS and in Fragile X patients. Then, we will repeat the same experiments using other previously described promising therapeutical molecules: the GS3K inhibitor lithium, the matrix metalloprotease 9 (MMP-9) inhibitor minocycline, and the anti-oxidant a-tocopherol and melatonin. Finally, we will evaluate the ability to rescue FXS phenotypic traits of molecules yet untested in the Fmr1-KO mouse, using MPEP as a standard. Notably, molecules targeting the GABAergic inhibitory pathway or the muscarinic cholinergic pathway will be tested in priority on Fmr1 knock-out animals, since we found evidence that these pathways are affected in FXS mouse model. We hope that this study will ultimately contribute to the development of novel therapeutical approaches for FXS patients.

We hope that this study will ultimately contribute to the development of novel therapeutic approaches for FXS patients.