Neurobiology of Disease Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase

Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegen-erative conditions like stroke anddementia.Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression.Wehypothesized that the pathogenicmechanisms includeuracilmisincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung/) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung/ embryonic fibroblasts, and conferred death of cultured Ung/ hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung/ but not Ung/mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidan