title: Extracellular superoxide dismutase is important for hippocampal neurogenesis and preservation of cognitive functions after irradiation.
abstract: Cranial irradiation is widely used in cancer therapy, but it often causes cognitive defects in cancer survivors. Oxidative stress is considered a major cause of tissue injury from irradiation. However, in an earlier study mice deficient in the antioxidant enzyme extracellular superoxide dismutase (EC-SOD KO) showed reduced sensitivity to radiation-induced defects in hippocampal functions. To further dissect the role of EC-SOD in neurogenesis and in response to irradiation, we generated a bigenic EC-SOD mouse model (OE mice) that expressed high levels of EC-SOD in mature neurons in an otherwise EC-SOD-deficient environment. EC-SOD deficiency was associated with reduced progenitor cell proliferation in the subgranular zone of dentate gyrus in KO and OE mice. However, high levels of EC-SOD in the granule cell layer supported normal maturation of newborn neurons in OE mice. Following irradiation, wild-type mice showed reduced hippocampal neurogenesis, reduced dendritic spine densities, and defects in cognitive functions. OE and KO mice, on the other hand, were largely unaffected, and the mice performed normally in neurocognitive tests. Although the resulting hippocampal-related functions were similar in OE and KO mice following cranial irradiation, molecular analyses suggested that they may be governed by different mechanisms: whereas neurotrophic factors may influence radiation responses in OE mice, dendritic maintenance may be important in the KO environment. Taken together, our data suggest that EC-SOD plays an important role in all stages of hippocampal neurogenesis and its associated cognitive functions, and that high-level EC-SOD may provide protection against irradiation-related defects in hippocampal functions.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94304, USA.
authors.forename: Yani
authors.initials: Y
authors.lastname: Zou
authors.forename: Rikki
authors.initials: R
authors.lastname: Corniola
authors.forename: David
authors.initials: D
authors.lastname: Leu
authors.forename: Aslam
authors.initials: A
authors.lastname: Khan
authors.forename: Peyman
authors.initials: P
authors.lastname: Sahbaie
authors.forename: Ayanabha
authors.initials: A
authors.lastname: Chakraborti
authors.forename: David J
authors.initials: DJ
authors.lastname: Clark
authors.forename: John R
authors.initials: JR
authors.lastname: Fike
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Huang
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D003071:Cognition / Q000528:radiation effects*; D003712:Dendrites / Q000378:metabolism / Q000528:radiation effects; D005110:Extracellular Space / Q000201:enzymology*; D006624:Hippocampus / Q000502:physiology* / Q000528:radiation effects*; D008568:Memory / Q000528:radiation effects; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000528:radiation effects; D055495:Neurogenesis / Q000528:radiation effects*; D011839:Radiation, Ionizing; D013482:Superoxide Dismutase / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D009414:Nerve Growth Factors; D014157:Transcription Factors; D013482:Superoxide Dismutase