Impact of genetic and nutritional disturbances in one-carbon metabolism on brain function and structure in mice

摘要: Homocystinuria can be caused by severe deficiency in either methylenetetrahydrofolate reductase (MTHFR) or methionine synthase (MTRR). Patients present with neurological symptoms, some of which include developmental delays, mental retardation, motor abnormalities and brain atrophy. Biochemically patients have reduced enzyme activity, hyperhomocysteinemia decreased levels serum folic acid, S-adenosylmethionine (SAM). Mouse models for genetic deficiencies MTHFR MTRR been developed to investigate the vivo effects these deficiencies. Young BALB/c Mthfr-/- mice elevated plasma homocysteine as well methylation SAM tissue. Mtrr is expressed developing neural tube expression increased tissue MTRR-deficient mice. The first two objectives this thesis will examine function adult male Adult C57BL/6 levels, impaired memory along changes hippocampus, including morphology, global DNA hypomethylation, altered choline metabolites acetyltransferase (ChAT) glucocorticoid receptor (GR). In cerebellum we confirmed morphological apoptosis previously described young Additionally, identified function, volume alterations cerebellum. deficient mildly short-term impairments, gait affective behavior hippocampus hippocampal volume. Changes metabolism cerebellum, liver were also identified.Maternal contributions MTHFR, acid during fetal early neonatal development are essential. last maternal on structure 3-week-old Mthfr+/+ offspring. Preliminary data suggests that lead Elevated offspring may responsible behavioural changes. Maternal (FADD) (ChDD) diets result ChDD results whereas FADD behaviors Both apoptosis, ChAT protein offspring.These behavioural, biochemical suggest folate critical development, maturation…