Intact corticostriatal function in aged system x- deficient mice.

Scientists studied older mice (equivalent to elderly humans) that were missing a brain protein called xCT. In younger mice, missing this protein caused autism-like behaviors and brain problems. However, in older mice, these issues disappeared - their brain function and social behaviors became normal. The missing protein may actually protect the aging brain from damage.

This animal study investigated age-related changes in corticostriatal brain function and autism-like behaviors in mice lacking the xCT protein, which regulates glutamate transport. While young adult xCT-deficient mice previously showed impaired brain connectivity and autism-like behaviors (repetitive behaviors, reduced social interaction), aged mice (16 months) did not display these deficits. In aged xCT-deficient mice, corticostriatal neurotransmission, brain structure, and glutamate levels were normalized compared to controls. Social and repetitive behaviors were also comparable between groups, with some reduction in aggressive behaviors in xCT-deficient mice.

The study suggests that xCT deficiency may actually protect against age-related brain changes through reduced advanced glycation end-products.

Findings suggest autism-related brain dysfunction may change with aging, potentially improving over time. However, this animal research requires human validation before clinical applications. May inform future research on aging trajectories in autism spectrum disorders.

Animal study findings may not translate to humans. Sample size not reported. Study design unclear. Limited to one specific genetic model. Short-term behavioral assessments may not capture all autism-relevant behaviors.

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 (xCTmice) 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 xCTmice 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 xCTand xCTmice, 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 xCTmice, 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 xCTmice, can protect the xCTbrain from age-related pathogenic alterations.