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Mol Psychiatry. 2019 Nov 14. doi: 10.1038/s41380-019-0584-0. [Epub ahead of print]

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

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Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, 171 64, Stockholm, Sweden.
Department of Developmental Neuroscience, New York State Psychiatric Institute, Columbia University, 1051 Riverside, New York, NY, 10032, USA.
Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, 171 64, Stockholm, Sweden.
Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, 467-8601, 1, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
Department of Neuroscience, Karolinska Institutet, Biomedicum, 171 77, Stockholm, Sweden.
Department of Protein Science, Division of Nanobiotechnology, KTH Royal Institute of Technology, Science for Life Laboratory, 171 21, Stockholm, Sweden.
Department of Human Biology, Faculty of Health Sciences, Anzio Road Observatory, 7925, University of Cape Town, Cape Town, South Africa.
Ludwig Institute for Cancer Research, Brussels Branch, Avenue Hippocrate 75, 1200, Brussels, Belgium.
National Bioinformatics Infrastructure Sweden (NIBIS), Science for Life Laboratory (SciLifeLab), Svante Arrhenius väg 16C, 106 91, Stockholm, Sweden.
Department of Biochemistry and Biophysics (DBB), Stockholm University, Svante Arrhenius väg 16C, 106 91, Stockholm, Sweden.
Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, BioClinicum J9:20, 171 64, Stockholm, Sweden.
Biology-Biochemistry Lab, Faculty of Nursing, School of Health Sciences, National and Kapodistrian University of Athens, Papadiamantopoulou 123, Goudi, 11527, Athens, Greece.
Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, 171 64, Stockholm, Sweden.
Pediatric Oncology, Karolinska University Hospital, Eugeniavägen 23, 171 64, Stockholm, Sweden.


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.


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