System xc- deficiency extends life-span and prevents age-related hippocampal dysfunction in mice
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1
Center for Neurosciences, Vrije University Brussel, Belgium
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2
Department of Neurosciences, Université de Mons, Belgium
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3
Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, United States
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4
Department of Medical Technology, Niigata University, Japan
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 inflammation1, both present in the diseased or aged brain2. This upregulation might induce or further drive neurological dysfunction, as it could decrease the threshold for glutamate toxicity (by releasing glutamate)3 and modulate neuroinflammation (by driving the pro-inflammatory microglial phenotype)4, 5. Although inhibition of system xc- has been proposed as a therapeutic strategy for diverse neurological disorders (some age-related), reports on its function in physiological aging are sparse.
We first studied the effect of genetic xCT deletion (xCT-/- mice) on life- and health-span. Next, we investigated the effect of aging on hippocampal xCT expression as well as the effect of xCT deletion on hippocampal aging (3-4 month versus 18-19-month old mice). As glutamate released via system xc- into the extrasynaptic space, could modulate synaptic transmission, we hypothesized that absence of system xc- might affect age-induced hippocampal deficits. We therefore compared age-related changes in hippocampal neurotransmission (slice electrophysiology), long-term potentiation (LTP) as well as hippocampus-dependent memory (Barnes maze, novel object location recognition task (NOLR)) between xCT-/- mice and their xCT+/+ littermates.
xCT-/- mice have an increased life-span without deterioration of health-span, compared to xCT+/+ mice. Next, although no age-induced changes in xCT protein expression were seen in the brain of xCT+/+ mice (C57BL/6J background; 3-4 month versus 20-24-month old mice), xCT mRNA was significantly increased in hippocampus of 13-month old compared to 9-month old SAMP8 mice (model for accelerated aging).
Aging prolongs the learning phase in the Barnes maze task for both genotypes. However, contrary to aged xCT+/+ mice and comparable to adult mice, the majority of aged xCT-/- mice use the hippocampus-dependent direct search strategy in the Barnes maze set-up at the end of the 5-day training session and they preserve this memory till 5 days after the last training session. In the NOLR, loss of system xc- induces impairment of spatial memory in adult mice. However, whereas aging negatively affects performance in the NOLR task in xCT+/+ mice, this was not the case for xCT-/- littermates and aged xCT-/- mice even perform better compared to adult xCT-/- mice. These data suggest that the hippocampal aging process is fundamentally different in mice lacking system xc-. In line with our behavioral data, basal hippocampal neurotransmission is indeed 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 demonstrate that absence of system xc- increases life-span and confers protection against age-related hippocampal dysfunction. Indeed, while system xc- seems to be important for hippocampal function in adult animals, it can become harmful during the aging process, thereby contributing to age-related memory decline.
References
1. Lewerenz J, Hewett SJ, Huang Y, et al. The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxidants & redox signaling. 2013;18(5):522-555.
2. Xia S, Zhang X, Zheng S, et al. An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment. Journal of immunology research. 2016;2016:8426874.
3. Massie A, Boillee S, Hewett S, et al. Main path and byways: non-vesicular glutamate release by system xc (-) as an important modifier of glutamatergic neurotransmission. Journal of neurochemistry. 2015;135(6):1062-1079.
4. Mesci P, Zaidi S, Lobsiger CS, et al. System xC- is a mediator of microglial function and its deletion slows symptoms in amyotrophic lateral sclerosis mice. Brain : a journal of neurology. 2015;138(Pt 1):53-68.
5. Albertini G, Deneyer L, Ottestad-Hansen S, et al. Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS-induced sickness and depressive-like behavior in mice. Glia. 2018;66(9):1845-1861.
Keywords:
System xc-,
Hippocampus,
Memory,
Aging,
slice electrophysiology
Conference:
13th National Congress of the Belgian Society for Neuroscience , Brussels, Belgium, 24 May - 24 May, 2019.
Presentation Type:
Poster presentation
Topic:
Behavioral/Systems Neuroscience
Citation:
Verbruggen
L,
Bentea
E,
Agnes
V,
Lara
O,
Ates
G,
De Bundel
D,
Sato
H,
Ris
L and
Massie
A
(2019). System xc- deficiency extends life-span and prevents age-related hippocampal dysfunction in mice.
Front. Neurosci.
Conference Abstract:
13th National Congress of the Belgian Society for Neuroscience .
doi: 10.3389/conf.fnins.2019.96.00028
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Received:
25 Apr 2019;
Published Online:
27 Sep 2019.
*
Correspondence:
Mx. Lise Verbruggen, Center for Neurosciences, Vrije University Brussel, Brussel, Brussels, Belgium, liverbru@vub.ac.be