Memantine prevents acute radiation-induced toxicities at hippocampal excitatory synapses

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 eGFP 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 post-synaptic markers vGLUT1 and PSD-95, were also analyzed. Neurons were pretreated with vehicle, the NMDA-type glutamate receptor antagonist memantine, or the glutamate scavenger glutamate pyruvate transaminase (GPT) 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.

Conclusions

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.