Memantine prevents acute radiation-induced toxicities at hippocampal excitatory synapses

Joseph G. Duman, Jeffrey Dinh, Wei Zhou, Henry Cham, Vasilis C. Mavratsas, Matea Pavešković, Shalaka Mulherkar, Susan L. McGovern, Kimberley F. Tolias, David R. Grosshans

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Background Memantine has shown clinical utility in preventing radiation-induced cognitive impairment, but the mechanisms underlying its protective effects remain unknown. We hypothesized that abnormal glutamate signaling causes radiation-induced abnormalities in neuronal structure and that memantine prevents synaptic toxicity. Methods Hippocampal cultures expressing enhanced green fluorescent protein were irradiated or sham-treated and their dendritic spine morphology assessed at acute (minutes) and later (days) times using high-resolution confocal microscopy. Excitatory synapses, defined by co-localization of the pre-and postsynaptic markers vesicular glutamate transporter 1 and postsynaptic density protein 95, were also analyzed. Neurons were pretreated with vehicle, the N-methyl-d-aspartate-type glutamate receptor antagonist memantine, or the glutamate scavenger glutamate pyruvate transaminase to assess glutamate signaling. For animal studies, Thy-1-YFP mice were treated with whole-brain radiotherapy or sham with or without memantine. Results Unlike previously reported long-term losses of dendritic spines, we found that the acute response to radiation is an initial increase in spines and excitatory synapses followed by a decrease in spine/synapse density with altered spine dynamics. Memantine pre-administration prevented this radiation-induced synaptic remodeling. Conclusion These results demonstrate that radiation causes rapid, dynamic changes in synaptic structural plasticity, implicate abnormal glutamate signaling in cognitive dysfunction following brain irradiation, and describe a protective mechanism of memantine.

Original languageEnglish
Pages (from-to)655-665
Number of pages11
JournalNeuro-oncology
Volume20
Issue number5
DOIs
StatePublished - Apr 9 2018

Keywords

  • memantine
  • radiation
  • synapse

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