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Lithium treatment reverses irradiation-induced changes in rodent neural progenitors and rescues cognition.

ABSTRACT: Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context. Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as antitumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation. Female mice received a single 4?Gy whole-brain radiation dose on postnatal day (PND) 21 and were randomized to 0.24% Li2CO₃ chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed on PND 77, 91, and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors, but neuronal integration occurred only after it was discontinued. Also, the treatment ameliorated deficits in spatial learning and memory retention observed in irradiated mice. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with microtubule stabilization, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced loss of hippocampal neurogenesis and cognitive impairment even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.

SUBMITTER: Zanni G

PROVIDER: S-EPMC7815512 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Lithium treatment reverses irradiation-induced changes in rodent neural progenitors and rescues cognition.

Zanni Giulia G Goto Shinobu S Fragopoulou Adamantia F AF Gaudenzi Giulia G Naidoo Vinogran V Di Martino Elena E Levy Gabriel G Dominguez Cecilia A CA Dethlefsen Olga O Cedazo-Minguez Angel A Merino-Serrais Paula P Stamatakis Antonios A Hermanson Ola O Blomgren Klas K

Molecular psychiatry 20191114 1

Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context. Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as antitumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation. Female mice received a single 4 Gy whole-brain radiation dose on postnatal day (PND ...[more]

PMID: 31723242

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Project description:In pediatric cancer survivors treated with whole-brain irradiation (WBI), long-term cognitive deficits and morbidity develop that are poorly understood and for which there is no treatment. We describe similar cognitive defects in juvenile WBI rats and correlate them with alterations in diffusion tensor imaging and magnetic resonance spectroscopy (MRS) during brain development.Juvenile Fischer rats received clinically relevant fractionated doses of WBI or a high-dose exposure. Diffusion tensor imaging and MRS were performed at the time of WBI and during the subacute (3-month) and late (6-month) phases, before behavioral testing.Fractional anisotropy in the splenium of the corpus callosum increased steadily over the study period, reflecting brain development. WBI did not alter the subacute response, but thereafter there was no further increase in fractional anisotropy, especially in the high-dose group. Similarly, the ratios of various MRS metabolites to creatine increased over the study period, and in general, the most significant changes after WBI were during the late phase and with the higher dose. The most dramatic changes observed were in glutamine-creatine ratios that failed to increase normally between 3 and 6 months after either radiation dose. WBI did not affect the ambulatory response to novel open field testing in the subacute phase, but locomotor habituation was impaired and anxiety-like behaviors increased. As for cognitive measures, the most dramatic impairments were in novel object recognition late after either dose of WBI.The developing brains of juvenile rats given clinically relevant fractionated doses of WBI show few abnormalities in the subacute phase but marked late cognitive alterations that may be linked with perturbed MRS signals measured in the corpus callosum. This pathomimetic phenotype of clinically relevant cranial irradiation effects may be useful for modeling, mechanistic evaluations, and testing of mitigation approaches.

Project description:Identification and characterization of mutations that drive cancer evolution constitute a major focus of cancer research. Consequently, dominant paradigms attribute the tumorigenic effects of carcinogens in general and ionizing radiation in particular to their direct mutagenic action on genetic loci encoding oncogenes and tumor suppressor genes. However, the effects of irradiation are not limited to genetic loci that encode oncogenes and tumor suppressors, as irradiation induces a multitude of other changes both in the cells and their microenvironment which could potentially affect the selective effects of some oncogenic mutations. P53 is a key tumor suppressor, the loss of which can provide resistance to multiple genotoxic stimuli, including irradiation. Given that p53 null animals develop T-cell lymphomas with high penetrance and that irradiation dramatically accelerates lymphoma development in p53 heterozygous mice, we hypothesized that increased selection for p53-deficient cells contributes to the causal link between irradiation and induction of lymphoid malignancies. We sought to determine whether ionizing irradiation selects for p53-deficient hematopoietic progenitors in vivo using mouse models. We found that p53 disruption does not provide a clear selective advantage within an unstressed hematopoietic system or in previously irradiated BM allowed to recover from irradiation. In contrast, upon irradiation p53 disruption confers a dramatic selective advantage, leading to long-term expansion of p53-deficient clones and to increased lymphoma development. Selection for cells with disrupted p53 appears to be attributable to several factors: protection from acute irradiation-induced ablation of progenitor cells, prevention of irradiation-induced loss of clonogenic capacity for stem and progenitor cells, improved long-term maintenance of progenitor cell fitness, and the disabling/elimination of competing p53 wild-type progenitors. These studies indicate that the carcinogenic effect of ionizing irradiation can in part be explained by increased selection for cells with p53 disruption, which protects progenitor cells both from immediate elimination and from long-term reductions in fitness following irradiation.

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Lithium treatment reverses irradiation-induced changes in rodent neural progenitors and rescues cognition.

Publications

Lithium treatment reverses irradiation-induced changes in rodent neural progenitors and rescues cognition.

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