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 language | English (US) |
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Pages (from-to) | 655-665 |
Number of pages | 11 |
Journal | Neuro-oncology |
Volume | 20 |
Issue number | 5 |
DOIs | |
State | Published - Apr 9 2018 |
Keywords
- memantine
- radiation
- synapse
ASJC Scopus subject areas
- Oncology
- Clinical Neurology
- Cancer Research