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Lithium treatment reverses irradiation-induced changes in rodent neural progenitors

Zanni Giulia, Goto Shinobu, Gaudenzi Giulia, Naidoo Vinogran, Levy Gabriel, Di Martino Elena, Dethlefsen Olga, Cedazo-Minguez Angel, Merino-Serrais Paula, Hermanson Ola, Blomgren Klas
doi: https://doi.org/10.1101/579235
Zanni Giulia
aChildren’s Hospital of Philadelphia (CHOP), Department of Anesthesiology and Critical Care Medicine, Perelman School of Medicine, Children’s Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104-4318
bKarolinska Institute, Department of Women’s and Children’s Health, Akademiska stråket 1, BioClinicum J9:30, 171 64 Solna, Sweden
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  • For correspondence: klas.blomgren@ki.se giulia.zanni85@gmail.com zannig@email.chop.edu
Goto Shinobu
bKarolinska Institute, Department of Women’s and Children’s Health, Akademiska stråket 1, BioClinicum J9:30, 171 64 Solna, Sweden
cNagoya City University Graduate School of Medical Sciences, Department of Obstetrics and Gynecology, 467- 8601, 1, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan
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Gaudenzi Giulia
dKarolinska Institute, Department of Neuroscience, Biomedicum, 17177, Stockholm, Sweden
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Naidoo Vinogran
eFaculty of Health Sciences, Department of Human Biology, Anzio Road Observatory, 7925, University of Cape Town, South Africa
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Levy Gabriel
fFaculté de Médecine Paris-Sud, 63 rue Gabriel Péri, 94276 Le Kremlin Bicêtre, Paris, France
gLudwig Institute for Cancer Research, Brussels Branch, Avenue Hippocrate 75, 1200 Brussels, Belgium
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Di Martino Elena
bKarolinska Institute, Department of Women’s and Children’s Health, Akademiska stråket 1, BioClinicum J9:30, 171 64 Solna, Sweden
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Dethlefsen Olga
hNational Bioinformatics Infrastructure Sweden (NIBIS), Science for Life Laboratory (SciLifeLab), Svante Arrhenius väg 16C, 106 91 Stockholm, Sweden
iStockholm University, Department of Biochemistry and Biophysics (DBB), Svante Arrhenius väg 16C, 106 91, Stockholm, Sweden
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Cedazo-Minguez Angel
jKarolinska Institute, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Novum, Blickgången 6, 14157 Huddinge, Sweden
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Merino-Serrais Paula
jKarolinska Institute, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Novum, Blickgången 6, 14157 Huddinge, Sweden
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Hermanson Ola
dKarolinska Institute, Department of Neuroscience, Biomedicum, 17177, Stockholm, Sweden
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Blomgren Klas
kKarolinska Institute, Department of Women’s and Children’s Health, Tomtebodavägen 18A, 8th floor, 171 77, Stockholm, Sweden
lKarolinska University Hospital, Pediatric Oncology, Eugeniavägen 23, 171 64 Solna, Sweden
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  • For correspondence: klas.blomgren@ki.se giulia.zanni85@gmail.com zannig@email.chop.edu
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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, and we previously showed that voluntary running introduced long after irradiation rescued hippocampal neurogenesis in young mice (Naylor et al. 2008a). Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as anti-tumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation, analogous to the voluntary running study. Female mice received a single 4 Gy whole-brain irradiation dose at postnatal day (PND) 21 and were randomized to 0.24% Li2CO3 chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed at PND 77, 91 and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors and promoted neuronal integration upon its discontinuation. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with proliferation, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced impairment of hippocampal neurogenesis 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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Posted March 16, 2019.
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Lithium treatment reverses irradiation-induced changes in rodent neural progenitors
Zanni Giulia, Goto Shinobu, Gaudenzi Giulia, Naidoo Vinogran, Levy Gabriel, Di Martino Elena, Dethlefsen Olga, Cedazo-Minguez Angel, Merino-Serrais Paula, Hermanson Ola, Blomgren Klas
bioRxiv 579235; doi: https://doi.org/10.1101/579235
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Lithium treatment reverses irradiation-induced changes in rodent neural progenitors
Zanni Giulia, Goto Shinobu, Gaudenzi Giulia, Naidoo Vinogran, Levy Gabriel, Di Martino Elena, Dethlefsen Olga, Cedazo-Minguez Angel, Merino-Serrais Paula, Hermanson Ola, Blomgren Klas
bioRxiv 579235; doi: https://doi.org/10.1101/579235

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