Persistent changes in neuronal structure and synaptic plasticity caused by proton irradiation

Abstract

Cranial radiotherapy is used routinely to control the growth of primary and secondary brain tumors, but often results in serious and debilitating cognitive dysfunction. In part due to the beneficial dose depth distributions that may spare normal tissue damage, the use of protons to treat CNS and other tumor types is rapidly gaining popularity. Astronauts exposed to lower doses of protons in the space radiation environment are also at risk for developing adverse CNS complications. To explore the consequences of whole body proton irradiation, mice were subjected to 0.1 and 1 Gy and analyzed for morphometric changes in hippocampal neurons 10 and 30 days following exposure. Significant dose-dependent reductions (~33%) in dendritic complexity were found, when dendritic length, branching and area were analyzed 30 days after exposure. At equivalent doses and times, significant reductions in the number (~30%) and density (50–75%) of dendritic spines along hippocampal neurons of the dentate gyrus were also observed. Immature spines (filopodia, long) exhibited the greatest sensitivity (1.5–3 fold) to irradiation, while more mature spines (mushroom) were more resistant to changes over a 1-month post-irradiation timeframe. Irradiated granule cell neurons spanning the subfields of the dentate gyrus showed significant and dose-responsive reductions in synaptophysin expression, while the expression of postsynaptic density protein (PSD-95) was increased significantly. These findings corroborate our past work using photon irradiation, and demonstrate for the first time, dose-responsive changes in dendritic complexity, spine density and morphology and synaptic protein levels following exposure to low dose whole body proton irradiation.

Dose- and ApoE Isoform-Dependent Cognitive Injury after Cranial56Fe Irradiation in Female Mice

“…Recent neuronal morphometry investigations using Golgi silver stain in mice and rats and fluorescence microscopy of transgenic mice expressing enhanced green fluorescent protein (EGFP) in neurons have demonstrated that γ-rays, protons, and 56 Fe radiation cause reductions in hippocampal neuron arborization (>50% at 30 days) as well as loss of dendritic spines, each of which would limit the complexity of signal processing (Chakraborti et al 2012;Parihar et al 2013;Quasem et al 2007). Parihar et al (2014Parihar et al ( , 2015b further showed reduction of dendritic complexity 10 and 30 days after 1 Gy of 250 MeV protons and spine reductions at ≥ 10 cGy. Immature filopodial spines were more sensitive than stubby or mushroom-shaped spines.…”

“…The age at evaluation and irradiation affects the responses to charged particles (Rabin et al 2012) and X-rays (Forbes et al 2014). Sex and genotype (e.g., ApoE allele and ATM) are important variables (Acevedo et al 2008;Benice and Raber 2009;Haley et al 2012;Higuchi et al 2002;Villasana et al 2006Villasana et al , 2011Yamamoto et al 2011;Yeiser et al 2013;Johnson et al 2014;Parihar et al 2014). Additionally, observations comparing head only-, body only-, or whole body-irradiated animals demonstrate a significant role for the periphery in determining behavioral responses .…”

Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain

“…Our past studies have shown that cranial irradiation could significantly disrupt components of neuronal architecture including dendritic length, volume, and complexity (13,14). To determine the potential impact of MV grafting on neuronal structure, Golgi-Cox-impregnated sections were used in detailed morphometric analyses of GCL neurons in the DG.…”

Stem Cell Transplantation Reverses Chemotherapy-Induced Cognitive Dysfunction

“…While past work has clearly defined the sensitivity of neurogenic populations of neural progenitor cells to radiation (14) and chemotherapeutic agents (4,15), it remains difficult to ascribe the spectrum of cognitive deficits to the loss of newly generated neurons in the hippocampus. Recent work analyzing the structure of newly born and mature hippocampal neurons has found irradiation (16,17) to elicit marked reductions in dendritic complexity spine density and synaptic protein levels. Morphologic alterations were temporally coincident with impaired cognition (18), suggesting a cause and effect between altered neuronal anatomy and cognitive function.…”