Quantitative Proteomic Analysis of the Hippocampus of Rats with GCR-Induced Spatial Memory Impairment

NASA is planning future missions to Mars, which will result in astronauts being exposed to ∼13 cGy/year of galactic cosmic radiation (GCR). Previous ground-based experiments have demonstrated that low (15 cGy) doses of 1 GeV/n ⁵⁶Fe ions impair hippocampus-dependent spatial memory in rats. However, some irradiated rats maintain a spatial memory performance comparable to that seen in the sham-irradiated rats, suggesting that some of these animals are able to ameliorate the deleterious effects of the GCR, while others are not. This rat model provides a unique opportunity to increase our understanding of how GCR affects neurophysiology, what adaptive responses can be invoked to prevent the emergence of GCR-induced spatial memory impairment, as well as the pathways that are altered when spatial memory impairment occurs. A label-free, unbiased proteomic profiling approach involving quantitative protein/peptide profiling followed by Cytoscape analysis has established the composition of the hippocampal proteome in male Wistar rats after exposure to 15 cGy of 1 GeV/n ⁵⁶Fe, and identified proteins whose expression is altered with respect to: 1. radiation exposure and 2. impaired spatial memory performance. We identified 30 proteins that were classified as "GCR exposure marker" (GEM) proteins (expressed solely or at higher levels in the irradiated rats but not related to spatial memory performance), most notably CD98, Cadps and GMFB. Conversely, there were 252 proteins that were detected only in the sham-irradiated samples, i.e., they were not detected in either of the irradiated cohorts; of these 10% have well-documented roles in neurotransmission. The second aspect of our data mining was to identify proteins whose expression was associated with either impaired or functional spatial memory. While there are multiple changes in the hippocampal proteome in the irradiated rats that have impaired spatial memory performance, with 203 proteins being detected (or upregulated) only in these rats, it would appear that spatial memory impairment may also arise from an inability of these rats to express "good spatial memory" (GSM) proteins, many of which play an important role in neuronal homeostasis and function, axonogenesis, presynaptic membrane organization and G-protein coupled receptor (GCPR) signaling. It may be possible to use this knowledge to develop two alternative countermeasure strategies, one that preserves critical pathways prophylactically and one that invokes restorative pathways after GCR exposure.