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We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (<jats:italic>Ung<\/jats:italic>\u2212\/\u2212) versus wild-type controls. Folate depletion increased nuclear mutation rates in<jats:italic>Ung<\/jats:italic>\u2212\/\u2212 embryonic fibroblasts, and conferred death of cultured<jats:italic>Ung<\/jats:italic>\u2212\/\u2212 hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in<jats:italic>Ung<\/jats:italic>\u2212\/\u2212 but not<jats:italic>Ung<\/jats:italic>+\/+ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in<jats:italic>Ung<\/jats:italic>\u2212\/\u2212 mice. Independent of<jats:italic>Ung<\/jats:italic>genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency.<\/jats:p>","DOI":"10.1523\/jneurosci.0940-08.2008","type":"journal-article","created":{"date-parts":[[2008,7,9]],"date-time":"2008-07-09T16:23:14Z","timestamp":1215620594000},"page":"7219-7230","source":"Crossref","is-referenced-by-count":100,"title":["Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase"],"prefix":"10.1523","volume":"28","author":[{"given":"Golo","family":"Kronenberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Harms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert 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