ALTERATION OF NEUROTRANSMITTERS IN THE BRAIN OF FMR1-KO MICE, A MODEL OF X-FRAGILE SYNDROME

Fragile X syndrome is a neurodevelopmental disorder representing the first monogenic cause of autism spectrum disorders. This syndrome, characterized by maladaptative behaviors and mental retardation, is due to a mutation on FMR1 gene localized on chromosome X. This mutation causes the suppression of the Fmrp protein, thereby altering synaptic process and plasticity. Nonetheless, previous data in the FMR1 KO mouse model reported few quantitative changes of neurotransmitters (monoamines, amino acids) across the brain in young or adult males. Here, we hypothesized that beyond quantitative changes of tissue neurotransmitters, correlative links of neurotransmitters across the brain are disorganized in male FMR1-KO mice at rest. Old (18-22 months), male FMR1 KO mice, known to present behavioral deficits, and littermate, were sacrificed. Twenty brain regions were collected to perform post-mortem quantification of monoamines [serotonin (5-HT), dopamine (DA), noradrenaline (NA), and metabolites] and amino-acids (glutamate, GABA, glutamine, glycine) using HPLC coupled to electrochemical detection. We identified in FMR1 KO mice a few changes of the quantities of neurotransmitters, metabolites, and turnover indexes (ratios metabolite/neurotransmitter or neurotransmitter/precursor) compared to wild-types, without specific signature. However, correlative analyses using the Pearson correlation coefficient r showed a high level of correlative links of turnover indexes (for 5-HT, DA, glutamate systems) between regions in wild-types, but not in FMR1 KO mice. The marked reduction of correlative links of the metabolism for several neurotransmitter systems across the brain in FMR1 KO mice suggests widespread alteration of neurotransmission that was underestimated when solely looking at neurotransmitter quantities.