title: C3 deficiency ameliorates the negative effects of irradiation of the young brain on hippocampal development and learning.
abstract: Radiotherapy in the treatment of pediatric brain tumors is often associated with debilitating late-appearing adverse effects, such as intellectual impairment. Areas in the brain harboring stem cells are particularly sensitive to irradiation (IR) and loss of these cells may contribute to cognitive deficits. It has been demonstrated that IR-induced inflammation negatively affects neural progenitor differentiation. In this study, we used mice lacking the third complement component (C3-/-) to investigate the role of complement in a mouse model of IR-induced injury to the granule cell layer (GCL) of the hippocampus. C3-/- and wild type (WT) mice received a single, moderate dose of 8 Gy to the brain on postnatal day 10. The C3-/- mice displayed 55 % more microglia (Iba-1+) and a trend towards increase in proliferating cells in the GCL compared to WT mice 7 days after IR. Importantly, months after IR C3-/- mice made fewer errors than WT mice in a reversal learning test indicating better learning capacity in C3-/- mice after IR. Notably, months after IR C3-/- and WT mice had similar GCL volumes, survival of newborn cells (BrdU), microglia (Iba-1) and astrocyte (S100β) numbers in the GCL. In summary, our data show that the complement system contributes to IR-induced loss of proliferating cells and maladaptive inflammatory responses in the acute phase after IR, leading to impaired learning capacity in adulthood. Targeting the complement system is hence promising for future strategies to reduce the long-term adverse consequences of IR in the young brain.
authors.affiliation: Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Kalm
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Andreasson
authors.affiliation: Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Björk-Eriksson
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.|Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.|Hunter Medical Research Institute, University of Newcastle, New South Wales, Australia.
authors.forename: Milos
authors.initials: M
authors.lastname: Pekny
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.|Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.|Hunter Medical Research Institute, University of Newcastle, New South Wales, Australia.
authors.forename: Marcela
authors.initials: M
authors.lastname: Pekna
authors.affiliation: Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Blomgren
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000378:metabolism / Q000528:radiation effects; D049109:Cell Proliferation / Q000235:genetics / Q000528:radiation effects; D003176:Complement C3 / Q000172:deficiency* / Q000235:genetics; D005260:Female; D006624:Hippocampus / Q000254:growth & development* / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D007858:Learning / Q000502:physiology* / Q000528:radiation effects; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000503:physiopathology; D013997:Time Factors
chemical_list: D003176:Complement C3
keywords: complement system; cranial radiotherapy; late effects; neurogenesis; neuroinflammation