1. Memantine prevents acute radiation-induced toxicities at hippocampal excitatory synapses.
- Author
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Duman JG, Dinh J, Zhou W, Cham H, Mavratsas VC, Paveškovic M, Mulherkar S, McGovern SL, Tolias KF, and Grosshans DR
- Subjects
- Abnormalities, Radiation-Induced etiology, Abnormalities, Radiation-Induced pathology, Animals, Cells, Cultured, Dendritic Spines pathology, Dendritic Spines radiation effects, Excitatory Amino Acid Antagonists pharmacology, Hippocampus pathology, Hippocampus radiation effects, Rats, Rats, Long-Evans, Receptors, N-Methyl-D-Aspartate metabolism, Synapses pathology, Synapses radiation effects, Abnormalities, Radiation-Induced prevention & control, Dendritic Spines drug effects, Gamma Rays adverse effects, Hippocampus drug effects, Memantine pharmacology, Synapses drug effects
- 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.
- Published
- 2018
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