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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- to 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.

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Acknowledgments

This work was supported by the National Institutes of Health NINDS Grant R01 NS074388 (CLL) and by NASA Grants NNX13AD59G and NNX10AD59G (CLL). We thank Vahan Martirosian, Nicole Chmielewski, Dr. Gregory Nelson, Tami Jones, and Mary Campbell-Beachler for excellent discussions and technical assistance.

Conflict of interest

The authors declare no conflicts of interest

Author information

Correspondence to Charles L. Limoli.

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Parihar, V.K., Pasha, J., Tran, K.K. et al. Persistent changes in neuronal structure and synaptic plasticity caused by proton irradiation. Brain Struct Funct 220, 1161–1171 (2015). https://doi.org/10.1007/s00429-014-0709-9

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Keywords

  • Dendritic complexity
  • Dendritic spines
  • Radiation-induced cognitive dysfunction
  • PSD-95
  • Synaptophysin