title: Neonatal Irradiation Leads to Persistent Proteome Alterations Involved in Synaptic Plasticity in the Mouse Hippocampus and Cortex.
abstract: Recent epidemiological data indicate that radiation doses as low as those used in computer tomography may result in long-term neurocognitive side effects. The aim of this study was to elucidate long-term molecular alterations related to memory formation in the brain after low and moderate doses of γ radiation. Female C57BL/6J mice were irradiated on postnatal day 10 with total body doses of 0.1, 0.5, or 2.0 Gy; the control group was sham-irradiated. The proteome analysis of hippocampus, cortex, and synaptosomes isolated from these brain regions indicated changes in ephrin-related, RhoGDI, and axonal guidance signaling. Immunoblotting and miRNA-quantification demonstrated an imbalance in the synapse morphology-related Rac1-Cofilin pathway and long-term potentiation-related cAMP response element-binding protein (CREB) signaling. Proteome profiling also showed impaired oxidative phosphorylation, especially in the synaptic mitochondria. This was accompanied by an early (4 weeks) reduction of mitochondrial respiration capacity in the hippocampus. Although the respiratory capacity was restored by 24 weeks, the number of deregulated mitochondrial complex proteins was increased at this time. All observed changes were significant at doses of 0.5 and 2.0 Gy but not at 0.1 Gy. This study strongly suggests that ionizing radiation at the neonatal state triggers persistent proteomic alterations associated with synaptic impairment.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Kempf
authors.affiliation: Department of Genetics, Erasmus Medical Center , 3015 CE Rotterdam, The Netherlands.
authors.forename: Sara
authors.initials: S
authors.lastname: Sepe
authors.forename: Christine
authors.initials: C
authors.lastname: von Toerne
authors.forename: Dirk
authors.initials: D
authors.lastname: Janik
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Hauck
authors.affiliation: Chair of Radiation Biology, Technical University Munich , 80333 Munich, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Atkinson
authors.affiliation: Department of Genetics, Erasmus Medical Center , 3015 CE Rotterdam, The Netherlands.
authors.forename: Pier G
authors.initials: PG
authors.lastname: Mastroberardino
authors.forename: Soile
authors.initials: S
authors.lastname: Tapio
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism / Q000528:radiation effects / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology / Q000528:radiation effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D036342:Ephrins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects*; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology / Q000528:radiation effects*; D017774:Long-Term Potentiation / Q000528:radiation effects*; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000528:radiation effects; D020543:Proteome / Q000235:genetics* / Q000378:metabolism; D009435:Synaptic Transmission / Q000528:radiation effects*; D013574:Synaptosomes / Q000378:metabolism / Q000528:radiation effects; D014916:Whole-Body Irradiation; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D045222:Electron Transport Chain Complex Proteins; D036342:Ephrins; C546976:MIRN132 microRNA, mouse; D035683:MicroRNAs; D009479:Neuropeptides; D020543:Proteome; C484602:Rac1 protein, mouse; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D020830:rac1 GTP-Binding Protein
keywords: Rac1; brain; cerebellum; dendritic spine; ionizing radiation; memory; miR-132; mitochondria; proteomics; synapse