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Using the Cre\u2010lox system, we developed two types of mouse mutants, <jats:italic>Fa2h<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice (<jats:italic>Fa2h<\/jats:italic> deleted in all cells by germline deletion) and <jats:italic>Fa2h<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> Cnp1\u2010Cre mice (<jats:italic>Fa2h<\/jats:italic> deleted only in oligodendrocytes and Schwann cells). We found significant demyelination, profound axonal loss, and abnormally enlarged axons in the CNS of <jats:italic>Fa2h<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice at 12 months of age, while structure and function of peripheral nerves were largely unaffected. <jats:italic>Fa2h<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice also exhibited histological and functional disruption in the cerebellum at 12 months of age. In a time course study, significant deterioration of cerebellar function was first detected at 7 months of age. Further behavioral assessments in water T\u2010maze and Morris water maze tasks revealed significant deficits in spatial learning and memory at 4 months of age. These data suggest that various regions of the CNS are functionally compromised in young adult <jats:italic>Fa2h<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice. The cerebellar deficits in 12\u2010month\u2010old <jats:italic>Fa2h<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> Cnp1\u2010Cre mice were indistinguishable from <jats:italic>Fa2h<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice, indicating that these phenotypes likely stem from the lack of myelin hFA\u2010galactolipids. In contrast, <jats:italic>Fa2h<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> Cnp1\u2010Cre mice did not show reduced performance in water maze tasks, indicating that oligodendrocytes are not involved in the learning and memory deficits found in <jats:italic>Fa2h<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice. These findings provide the first evidence that FA2H has an important function outside of oligodendrocytes in the CNS. \u00a9 2011 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/glia.21172","type":"journal-article","created":{"date-parts":[[2011,4,14]],"date-time":"2011-04-14T00:23:36Z","timestamp":1302740616000},"page":"1009-1021","source":"Crossref","is-referenced-by-count":128,"title":["Central nervous system dysfunction in a mouse model of Fa2h deficiency"],"prefix":"10.1002","volume":"59","author":[{"given":"Kathleen A.","family":"Potter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael 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