032.18. System xc--deficiency prevents age-related hippocampal dysfunction in mice

System xc-, with xCT as specific subunit, is an astrocytic antiporter that imports cystine in exchange for glutamate. System xc- is enhanced following oxidative stress and inflammation, both present in the aged brain. While we could not detect changes in xCT protein expression in the hippocampus of aged (20-24-month old) compared to adult (3-4-month old) C57BL/6 mice, xCT mRNA was significantly increased in hippocampus of 13-month old compared to 9-month old SAMP8 mice (model for accelerated aging). As system xc- releases glutamate into the extrasynaptic space, changes in its function can modulate glutamatergic neurotransmission. Moreover, enhancement of system xc- might induce neurological dysfunction, as it could decrease the threshold for glutamate toxicity (by releasing glutamate) and modulate neuroinflammation (by driving the pro-inflammatory microglial phenotype). We therefore investigated the role of system xc¬- in hippocampal function and how it can affect age-related hippocampal impairment. In the Barnes maze set-up, a behavioral test used for evaluating hippocampal function, adult xCT+/+ and xCT-/- mice show identical spatial learning and memory capacities. However, contrary to aged xCT+/+ mice, the majority of aged xCT-/- mice learn to use the hippocampus-dependent direct search strategy in the Barnes maze set-up and they preserve this memory till 5 days after the last training session, comparable to adult mice. In the novel object location recognition task, loss of system xc- induces impairment of spatial memory in adult mice. However, whereas aging negatively affects performance of xCT+/+ mice in this task, aged xCT-/- mice perform better compared to adult xCT-/- mice. In line with these behavioral data, basal hippocampal neurotransmission is reduced in adult xCT-/- mice, while the age-related decrease in basal synaptic transmission as well as the age-induced changes in LTP that are observed in xCT+/+ mice, are prevented in the absence of system xc-. To conclude, our results show that the hippocampal aging process is fundamentally different in mice lacking system xc-. While system xc- seems to be important for certain aspects of hippocampal function in adult animals, it can become harmful during the aging process and contribute to age-related memory decline.