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Central nervous system dysfunction in a mouse model of Fa2h deficiency
Author(s) -
Potter Kathleen A.,
Kern Michael J.,
Fullbright George,
Bielawski Jacek,
Scherer Steven S.,
Yum Sabrina W.,
Li Jian J.,
Cheng Hua,
Han Xianlin,
Venkata Jagadish Kummetha,
Akbar Ali Khan P.,
Rohrer Bärbel,
Hama Hiroko
Publication year - 2011
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.21172
Subject(s) - morris water navigation task , biology , leukodystrophy , water maze , neurodegeneration , myelin , cerebellum , galactolipids , neuroscience , rotarod performance test , central nervous system , endocrinology , medicine , biochemistry , gene , hippocampus , motor activity , disease , chloroplast
Fatty acid 2‐hydroxylase (FA2H) is responsible for the synthesis of myelin galactolipids containing hydroxy fatty acid (hFA) as the N ‐acyl chain. Mutations in the FA2H gene cause leukodystrophy, spastic paraplegia, and neurodegeneration with brain iron accumulation. Using the Cre‐lox system, we developed two types of mouse mutants, Fa2h −/− mice ( Fa2h deleted in all cells by germline deletion) and Fa2h flox/flox Cnp1‐Cre mice ( Fa2h deleted only in oligodendrocytes and Schwann cells). We found significant demyelination, profound axonal loss, and abnormally enlarged axons in the CNS of Fa2h −/− mice at 12 months of age, while structure and function of peripheral nerves were largely unaffected. Fa2h −/− 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‐maze 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 Fa2h −/− mice. The cerebellar deficits in 12‐month‐old Fa2h flox/flox Cnp1‐Cre mice were indistinguishable from Fa2h −/− mice, indicating that these phenotypes likely stem from the lack of myelin hFA‐galactolipids. In contrast, Fa2h flox/flox Cnp1‐Cre mice did not show reduced performance in water maze tasks, indicating that oligodendrocytes are not involved in the learning and memory deficits found in Fa2h −/− mice. These findings provide the first evidence that FA2H has an important function outside of oligodendrocytes in the CNS. © 2011 Wiley‐Liss, Inc.