Longitudinal in vivo developmental changes of metabolites in the hippocampus of Fmr1 knockout mice

摘要

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is studied in the Fmr1 knockout (KO) mouse, which models both the anatomical and behavioral changes observed in FXS patients. In vitro studies have shown many alterations in synaptic plasticity and increased density of immature dendritic spines in the hippocampus, a region involved in learning and memory. In this study, magnetic resonance imaging (MRI) and 1H magnetic resonance spectroscopy (MRS) were used to determine in vivo longitudinal changes in volume and metabolites in the hippocampus during the critical period of early myelination and synaptogenesis at post-natal days (PND) 18, 21, and 30 in Fmr1 KO mice compared with wild-type (WT) controls. MRI demonstrated an increase in volume of the hippocampus in the Fmr1 KO mouse compared with controls. MRS revealed significant developmental changes in the ratios of hippocampal metabolites N-acetylaspartate (NAA), myo-inositol (Ins), and taurine to total creatine (tCr) in Fmr1 KO mice compared with WT controls. Ins was decreased at PND 30, and taurine was increased at all ages studied in Fmr1 KO mice compared with controls. An imbalance of brain metabolites in the hippocampus of Fmr1 KO mice during the critical developmental period of synaptogenesis and early myelination could have long-lasting effects that adversely affect brain development and contribute to ongoing alterations in brain function. Fragile X syndrome is the most common inherited cause of mental retardation, often studied in Fmr1 knockout (KO) mice. Comparison of Fmr1 KO to wild type mice at postnatal days 18, 21, and 30 using in vivo MRI/MRS showed alterations of NAA, taurine and inositol in the developing hippocampus. These alterations could change osmoregulation, signal transduction and neuromodulation during synaptogenesis and early myelination which could contribute to the impaired CNS function in fragile X syndrome.