The astrocytic cystine/glutamate antiporter system xc− represents an important source of extracellular glutamate in the central nervous system, with potential impact on excitatory neurotransmission. Yet, its function and importance in brain physiology remain incompletely understood. Employing slice electrophysiology and mice with a genetic deletion of the specific subunit of system xc−, xCT (xCT−/− mice), we uncovered decreased neurotransmission at corticostriatal synapses. This effect was partly mitigated by replenishing extracellular glutamate levels, indicating a defect linked with decreased extracellular glutamate availability. We observed no changes in the morphology of striatal medium spiny neurons, the density of dendritic spines, or the density or ultrastructure of corticostriatal synapses, indicating that the observed functional defects are not due to morphological or structural abnormalities. By combining electron microscopy with glutamate immunogold labeling, we identified decreased intracellular glutamate density in presynaptic terminals, presynaptic mitochondria, and in dendritic spines of xCT−/− mice. A proteomic and kinomic screen of the striatum of xCT−/− mice revealed decreased expression of presynaptic proteins and abnormal kinase network signaling, that may contribute to the observed changes in postsynaptic responses. Finally, these corticostriatal deregulations resulted in a behavioral phenotype suggestive of autism spectrum disorder in the xCT−/− mice; in tests sensitive to corticostriatal functioning we recorded increased repetitive digging behavior and decreased sociability. To conclude, our findings show that system xc− plays a previously unrecognized role in regulating corticostriatal neurotransmission and influences social preference and repetitive behavior.

Long-term potentiation (LTP) is a type of synaptic plasticity characterized by an increase in synaptic strength and believed to be involved in memory encoding. LTP elicited in the CA1 region of acute hippocampal slices has been extensively studied. However the molecular mechanisms underlying the maintenance phase of this phenomenon are still poorly understood. This could be partly due to the various experimental conditions used by different laboratories. Indeed, the maintenance phase of LTP is strongly dependent on external parameters like oxygenation, temperature and humidity. It is also dependent on internal parameters like orientation of the slicing plane and slice viability after dissection.The optimization of all these parameters enables the induction of a very reproducible and very stable long-term potentiation. This methodology offers the possibility to further explore the molecular mechanisms involved in the stable increase in synaptic strength in hippocampal slices. It also highlights the importance of experimental conditions in in vitro investigation of neurophysiological phenomena. Video LinkThe video component of this article can be found at

The cystine/glutamate antiporter system xc− has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and genetic deletion of its specific subunit xCT (xCT−/−) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT−/− mice led to the hypothesis that system xc− deletion would negatively affect life- and healthspan. Still, till now the role of system xc− in physiological aging remains unexplored. We therefore studied the effect of xCT deletion on the aging process of mice, with a particular focus on the immune system, hippocampal function, and cognitive aging. We observed that male xCT−/− mice have an extended lifespan, despite an even more increased plasma cystine/cysteine ratio in aged compared to adult mice. This oxidative shift does not negatively impact the general health status of the mice. On the contrary, the age-related priming of the innate immune system, that manifested as increased LPS-induced cytokine levels and hypothermia in xCT+/+ mice, was attenuated in xCT−/− mice. While this was associated with only a very moderate shift towards a more anti-inflammatory state of the aged hippocampus, we observed changes in the hippocampal metabolome that were associated with a preserved hippocampal function and the retention of hippocampus-dependent memory in male aged xCT−/− mice. Targeting system xc− is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging.

Deformation, compression, or stretching of brain tissues cause diffuse axonal injury (DAI) and induce structural and functional alterations of astrocytes, the most abundant cell type in the brain. To gain further insight into the role of mechanically activated astrocytes on neuronal networks, this study was designed to investigate whether cytokines released by mechanically activated astrocytes can affect the growth and synaptic connections of cortical neuronal networks. Astrocytes were cultivated on elastic membranes and subjected to repetitive mechanical insults, whereas well-defined protein micropatterns were used to form standardized neuronal networks. GFAP staining showed that astrocytes were mechanically activated after two cycles of stretch and mesoscale discovery assays indicated that injured astrocytes released four major cytokines. To understand the role of these cytokines, neuronal networks were cultured with the supernatant of healthy or mechanically activated astrocytes, and the individual contribution of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) was studied. We found that the supernatant of two-cycle stretched astrocytes decreased presynaptic terminals and indicated that TNF-α must be considered a key player of the synaptic loss. Furthermore, our results indicate that cytokines released by injured astrocytes significantly modulate the balance between TNFR1 and TNFR2 receptors by enhancing R2 receptors. We demonstrated that TNF-α is not involved in this process, suggesting a predominant role of other secreted cytokines. Together, these results contribute to a better understanding of the consequences of repetitive astrocyte deformations and highlight the role of inflammatory signaling pathways in synaptic plasticity and modulation of TNFR1 and TNFR2 receptors.

Worldwide, approximately 27 million people are affected by Alzheimer’s disease (AD). AD pathophysiology is believed to be caused by the deposition of the β-amyloid peptide (Aβ). Aβ can reduce long-term potentiation (LTP), a form of synaptic plasticity that is closely associated with learning and memory and involves postsynaptic glutamate receptor phosphorylation and trafficking. Moreover, Aβ seems to be able to reduce glutamatergic transmission by increasing the endocytosis of NMDA receptors. Trace amines (TAs) are biogenic amines that are structurally similar to monoamine neurotransmitters. TAs bind to G protein-coupled receptors, called TAARs (trace amine-associated receptors); the best-studied member of this family, TAAR1, is distributed in the cortical and limbic structures of the CNS. It has been shown that the activation of TAAR1 can rescue glutamatergic hypofunction and that TAAR1 can modulate glutamate NMDA receptor-related functions in the frontal cortex. Several lines of evidence also suggest the pro-cognitive action of TAAR1 agonists in various behavioural experimental protocols. Thus, we studied, in vitro, the role of the TAAR1 agonist RO5256390 on basal cortical glutamatergic transmission and tested its effect on Aβ-induced dysfunction. Furthermore, we investigated, in vivo, the role of TAAR1 in cognitive dysfunction induced by Aβ infusion in Aβ-treated mice. In vitro data showed that Aβ 1–42 significantly decreased NMDA cell surface expression while the TAAR1 agonist RO5256390 promoted their membrane insertion in cortical cells. In vivo, RO5256390 showed a mild pro-cognitive effect, as demonstrated by the better performance in the Y maze test in mice treated with Aβ. Further studies are needed to better understand the interplay between TAAR1/Aβ and glutamatergic signalling, in order to evaluate the eventual beneficial effect in different experimental paradigms and animal models. Taken together, our data indicate that TAAR1 agonism may provide a novel therapeutic approach in the treatments of disorders involving Aβ-induced cognitive impairments, such as AD.