Spatial Learning and Memory Deficits after Whole-Brain Irradiation are Associated with Changes in NMDA Receptor Subunits in the Hippocampus

Abstract

Whole-brain irradiation is used for the treatment of brain tumors, but can it also induce neural changes, with progressive dementia occurring in 20-50% of long-term survivors. The present study investigated whether 45 Gy of whole-brain irradiation delivered to 12-month-old Fischer 344 x Brown Norway rats as nine fractions over 4.5 weeks leads to impaired Morris water maze (MWM) performance 12 months later. Compared to sham-irradiated rats, the irradiated rats demonstrated impaired MWM performance. The relative levels of the NR1 and NR2A but not the NR2B subunits of the NMDA receptor were significantly higher in hippocampal CA1 of irradiated rats compared to control rats. No significant differences were detected for these NMDA subunits in CA3 or dentate gyrus. Further analysis of CA1 revealed that the relative levels of the GluR1 and GluR2 subunits of the AMPA receptor and synaptophysin were not altered by whole-brain irradiation. In summary, a clinically relevant regimen of fractionated whole-brain irradiation led to significant impairments in spatial learning and reference memory and alterations in the relative levels of subunits of the NMDA, but not the AMPA, receptors in hippocampal CA1. These findings suggest for the first time that radiation-induced cognitive impairments may be associated with alterations in glutamate receptor composition.

Structural MRI research in patients with nasopharyngeal carcinoma following radiotherapy: A DTI and VBM study

“…Although a limited number of neurons died following radiation, the dysfunction in axons and synapses may induce central nervous system damage (28). In addition, radiation may eliminate oligodendrocytes (29), resulting in a decrease in GM volume.…”

An Experimental Study of Acute Radiation-Induced Cognitive Dysfunction in a Young Rat Model

“…Shi et al 24 found that the relative levels of certain subtypes of the N-methyl D-aspartate receptor were significantly higher in the hippocampal cornu ammonis 1 (CA1) region of irradiated rats compared with control rats after whole-brain radiation, indicating a possible involvement of an altered glutamate neurotransmission and/or excitatory neurotoxicity in radiation-induced cognitive impairments. Other mechanisms, such as the death of parenchymal and vascular cells, and even the inhibition of the formation of new neurons in the hippocampus, could also be involved.…”

Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence

“…As a result, up to 50% of patients who survive long term after treatment experience progressive dementia, thus severely compromising quality of life . The available experimental data clearly demonstrate that radiation also leads to a progressive impairment of cognitive function in animal models, mimicking the clinical scenario of cognitive decline in patients after WBI (Lamproglou et al 2001;Shi et al 2006;Soussain et al 2009;Warrington et al 2012;Welzel et al 2008aWelzel et al , 2008b. Recent studies show that in addition to its profound harmful effects on cognitive function, WBI can also result in the impairment of other brain functions such as coordination of gait (Hatcher-Martin and Factor 2016).…”