title: Paradoxical relationship between Mn superoxide dismutase deficiency and radiation-induced cognitive defects.
abstract: Radiation therapy of the CNS, even at low doses, can lead to deficits in neurocognitive functions. Reduction in hippocampal neurogenesis is usually, but not always, associated with cognitive deficits resulting from radiation therapy. Generation of reactive oxygen species is considered the main cause of radiation-induced tissue injuries, and elevated levels of oxidative stress persist long after the initial cranial irradiation. Consequently, mutant mice with reduced levels of the mitochondrial antioxidant enzyme, Mn superoxide dismutase (MnSOD or Sod2), are expected to be more sensitive to radiation-induced changes in hippocampal neurogenesis and the related functions. In this study, we showed that MnSOD deficiency led to reduced generation of immature neurons in Sod2-/+ mice even though progenitor cell proliferation was not affected. Compared to irradiated Sod2+/+ mice, which showed cognitive defects and reduced differentiation of newborn cells towards the neuronal lineage, irradiated Sod2-/+ mice showed normal hippocampal-dependent cognitive functions and normal differentiation pattern for newborn neurons and astroglia. However, we also observed a disproportional decrease in newborn neurons in irradiated Sod2-/+ following behavioral studies, suggesting that MnSOD deficiency may render newborn neurons more sensitive to stress from behavioral trainings following cranial irradiation. A positive correlation between normal cognitive functions and normal dendritic spine densities in dentate granule cells was observed. The data suggest that maintenance of synaptic connections, via maintenance of dendritic spines, may be important for normal cognitive functions following cranial irradiation.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Rikki
authors.initials: R
authors.lastname: Corniola
authors.forename: Yani
authors.initials: Y
authors.lastname: Zou
authors.forename: David
authors.initials: D
authors.lastname: Leu
authors.forename: John R
authors.initials: JR
authors.lastname: Fike
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Huang
mesh_terms: D000818:Animals; D001007:Anxiety; D049109:Cell Proliferation / Q000528:radiation effects; D003072:Cognition Disorders / Q000209:etiology*; D003213:Conditioning, Psychological; D049229:Dendritic Spines / Q000528:radiation effects; D005239:Fear; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects; D018782:Maze Learning; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D055495:Neurogenesis / Q000528:radiation effects; D018384:Oxidative Stress; D011833:Radiation Injuries, Experimental; D013482:Superoxide Dismutase / Q000172:deficiency*
chemical_list: D013482:Superoxide Dismutase