Journal Article

Intact corticostriatal function in aged system x c - - deficient mice

Arckens, Lutgarde, Moore, Cindy, Lara, Olaya, Ates, Gamze, De Pauw, Laura, Villers, Agnès, Sato, Hideyo, Bentea, Eduard, Vanonckelen, Océane, Verbruggen, Lise, Massie, Ann, Ris, Laurence, Meshul, Charles K

2025

Overview

System x (with xCT as specific subunit) is an astrocytic cystine/glutamate antiporter that constitutes the major source of extracellular glutamate in the mouse striatum. We previously reported that young-adult mice lacking xCT (xCT mice) display decreased intracellular glutamate levels in pre- and post-synaptic compartments at corticostriatal synapses as well as impaired corticostriatal neurotransmission, compared to wildtype (xCT ) littermates. These changes were accompanied by increased repetitive behavior and reduced social interaction, typical behaviors related to autism spectrum disorder (ASD). Although ASD is reported to be associated with atypical brain aging, we recently showed that xCT mice are protected against age-related hippocampal decline. Therefore, we here investigated whether the corticostriatal impairments and associated ASD-like behavior would be maintained in aged (16-months-old) mice. Genetic deletion of xCT does not affect corticostriatal neurotransmission in aged mice or the morphology of medium-spiny neurons. Except for a slight decrease in synaptic cleft width, the ultrastructure of corticostriatal synapses and intracellular glutamate levels are unaltered in the absence of xCT in aged mice. Accordingly, repetitive and social explorative behavior were comparable between aged xCT and xCT mice, while the latter showed a reduction in interactions that could be classified as being aggressive or dominant. To conclude, contrary to our previous observations in young-adult mice, corticostriatal neurotransmission and social behavior are no longer impaired in aged xCT mice, most likely because intracellular glutamate levels are no longer different. Moreover, the reduced levels of advanced glycation end-products that we observed in striatal tissue of xCT mice, can protect the xCT brain from age-related pathogenic alterations.

• Subject: Aging - physiology / Amino Acid Transport System y+ - deficiency / Amino Acid Transport System y+ - genetics / Animals / Autism Spectrum Disorder - genetics / Autism Spectrum Disorder - metabolism / Autism Spectrum Disorder - physiopathology / Behavior, Animal - physiology / Cerebral Cortex - metabolism / Cerebral Cortex - physiopathology / Corpus Striatum - metabolism / Corpus Striatum - physiopathology / Glutamic Acid - metabolism / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Synapses - metabolism / Synapses - ultrastructure / Synaptic Transmission - physiology