title: Cranial irradiation compromises neuronal architecture in the hippocampus.
abstract: Cranial irradiation is used routinely for the treatment of nearly all brain tumors, but may lead to progressive and debilitating impairments of cognitive function. Changes in synaptic plasticity underlie many neurodegenerative conditions that correlate to specific structural alterations in neurons that are believed to be morphologic determinants of learning and memory. To determine whether changes in dendritic architecture might underlie the neurocognitive sequelae found after irradiation, we investigated the impact of cranial irradiation (1 and 10 Gy) on a range of micromorphometric parameters in mice 10 and 30 d following exposure. Our data revealed significant reductions in dendritic complexity, where dendritic branching, length, and area were routinely reduced (>50%) in a dose-dependent manner. At these same doses and times we found significant reductions in the number (20-35%) and density (40-70%) of dendritic spines on hippocampal neurons of the dentate gyrus. Interestingly, immature filopodia showed the greatest sensitivity to irradiation compared with more mature spine morphologies, with reductions of 43% and 73% found 30 d after 1 and 10 Gy, respectively. Analysis of granule-cell neurons spanning the subfields of the dentate gyrus revealed significant reductions in synaptophysin expression at presynaptic sites in the dentate hilus, and significant increases in postsynaptic density protein (PSD-95) were found along dendrites in the granule cell and molecular layers. These findings are unique in demonstrating dose-responsive changes in dendritic complexity, synaptic protein levels, spine density and morphology, alterations induced in hippocampal neurons by irradiation that persist for at least 1 mo, and that resemble similar types of changes found in many neurodegenerative conditions.
authors.affiliation: Department of Radiation Oncology, University of California, Irvine, CA 92697-2695, USA.
authors.forename: Vipan Kumar
authors.initials: VK
authors.lastname: Parihar
authors.forename: Charles L
authors.initials: CL
authors.lastname: Limoli
mesh_terms: D000818:Animals; D016371:Cranial Irradiation / Q000009:adverse effects*; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D000076122:Disks Large Homolog 4 Protein; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000528:radiation effects; D051528:Guanylate Kinases / Q000096:biosynthesis; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D009415:Nerve Net / Q000473:pathology / Q000528:radiation effects; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000473:pathology; D016708:Synaptophysin / Q000096:biosynthesis
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D016708:Synaptophysin; C569015:Syp protein, mouse; D051528:Guanylate Kinases
keywords: radiation injury; radiation-induced cognitive dysfunction; structural plasticity