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.
Highlights
Radiation therapy is commonly used in the treatment of malignant brain tumors, and effective, the dose that can be administered safely is limited due to potential injury to normal tissues [1,2,3,4]
In this report we showed that a 50% reduction in MnSOD altered baseline hippocampal neurogenesis and the response of these newly born cells to cranial irradiation in Sod22/+ mice
Even though irradiated Sod22/+ mice had a marked reduction in the number of new neurons following behavioral studies, these mice were able to maintain a similar level of performance as sham irradiated Sod22/+ mice in studies designed to test the hippocampal-dependent functions of learning and memory
Summary
Radiation therapy is commonly used in the treatment of malignant brain tumors, and effective, the dose that can be administered safely is limited due to potential injury to normal tissues [1,2,3,4]. Radiation injury to the brain can involve multiple regions and a variety of cell/tissue types, leading to variable degrees of motor and cognitive dysfunctions [4]. Studies with experimental animals and humans suggest that the production of new neurons, (i.e. neurogenesis) continues in limited brain regions throughout the entire adult life [5,6,7]. Cranial irradiation therapy can have a strong negative impact on hippocampal neurogenesis and its associated functions of learning and memory
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