Corticostriatal dysfunction and social interaction deficits in mice lacking the cystine/glutamate antiporter

Abstract

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.

Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders

“…This transport system is necessary for redox balance and regulation of extracellular glutamate concentrations [188] by cooperating with excitatory glutamate transporters [189]. The deletion of xCT in mice produced less presynaptic mitochondria in the dorsolateral striatum and behavioral deficits associated with ASD [190]. This study highlights the significant role of astrocytes in ASD.…”

“…Understanding how synaptic mitochondria contribute to different neuronal populations in disease states could help to elucidate and develop novel therapeutic options to treat ASD and ASD-related neurodevelopmental disorders more effectively. [190] Reduced presynaptic mitochondrial population…”

Proteomic insights into synaptic signaling in the brain: the past, present and future

“…Proteomics has long played an indispensable role in the discovery and verification of biomarkers for brain disorders [ 17 ], and studies are increasingly oriented towards exploring the pathological mechanisms underlying various brain disorders. In a recently published work, researchers found that the astrocytic cystine/glutamate antiporter system xc(-) regulated corticostriatal neurotransmission, and influenced social preference and repetitive behavior in mice, providing important clues toward the neural mechanisms related to ASD and obsessive–compulsive disorder [ 226 ]. Synaptic proteome abnormalities related to several psychiatric disorders have been revealed in the last decade, and a number of signaling pathways are involved [ 54 , 160 , 227 , 228 ].…”

KRSA: Network-based Prediction of Differential Kinase Activity from Kinome Array Data

“…This method has been applied to multiple datasets and predictions have been experimentally validated in our laboratory through individual kinase activity assays and inhibitor studies (Bentea et al, 2019;Bentea et al, 2020;Dorsett et al, 2017;Flaherty et al, 2019;McGuire et al, 2017;Schrode et al, 2019). An early version of KRSA, containing only the random sampling algorithm, identified altered phosphorylation of peptides and subsequently perturbed kinase activity in the anterior cingulate cortex (ACC) between schizophrenia and control subjects (McGuire et al, 2017).…”

“…KRSA also was used to analyze kinome signatures of genetic perturbation of NRXN1 and FURIN1 in human induced pluripotent stem cell (hiPSC)-derived neurons (Flaherty et al, 2019;. More recently, KRSA has been utilized to analyze the kinome signature of mice with a genetic deletion of a specific subunit of cystine/glutamate antiporter system (xCT −/− mice) (Bentea et al, 2020). All of these published studies required significant use of multiple tools, some closed-access, and statistical expertise for quality control, network growth, pathway enrichment, and manually created graphs, heatmaps, and networks for visualization purposes.…”