Alterations in brain metabolism using Proton Magnetic Resonance Spectroscopy (1H-MRS) in mice after Rho GTPases pharmacological modulation

The RhoGTPases, proteins that regulate actin cytoskeleton, in the Central Nervous System have a crucial role on neuronal plasticity and have been linked to neurodegenerative and neurodevelopmental disorders, focussing on cognitive and, more recently motor functions. Here, we pharmacologically modulated RhoGTPases pathways by administering fasudil, an inhibitor of the RhoA downstream effectors Rho kinases (ROCKs). The aim of this work was to evaluate the effects of ROCKs inhibition on motor behaviour, brain metabolism and structure. CD1 five-months-old male mice were divided into 2 groups: fasudil (100 mg/Kg/d in drinking water for three months) and controls. After treatment and behavioural tests on locomotion and motor coordination (open field task and rotarod), MRI/MRS experiments were performed on a small animal system (Pharmascan 7.0 T, Bruker) equipped with a cryo-probe. Brain metabolism was analysed by quantitative MRS in the motor cortex and cerebellum, evaluating possible somatosensory alterations and deficits in motor coordination. Finally, structure alterations were studied by DTI (30 gradient directions). MRS shows an increase of glutamate in the motor cortex of fasudil-treated mice. Also, fasudil increases total choline content in both brain regions examined and creatine/phosphocreatine ratio in the cerebellum. The decrease in phosphocreatine could be indicative of a higher brain energy consumption; these metabolic alterations, however, were not paralleled by motor coordination or locomotor activity impairments. Further studies are warranted to clarify whether brain metabolism alterations induced by chronic fasudil treatment may have effects on more subtle motor functions or additional behavioural domains. Reference: Bianca De Filippis, Alessia Fabbri, Daiana Simone, Rossella Canese, Laura Ricceri, Fiorella Malchiodi-Albedi, Giovanni Laviola, and Carla Fiorentini, 2012, Modulation of RhoGTPases Improves the Behavioral Phenotype and Reverses Astrocytic Deficits in a Mouse Model of Rett Syndrome, Neuropsychopharmacology.