Hyperexcitability and brain morphological differences in mice lacking the cystine/glutamate antiporter, system xc

• Published in: Journal of neuroscience research Vol. 99; no. 12; pp. 3339 - 3353
• Main Authors: Sears, Sheila M. S., Roberts, Sarah H., Hewett, Sandra J.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc 01.12.2021
• Subjects: Astrocytes; Brain; Central nervous system; Corpus callosum; Cortex (motor); Cystine; Dendritic spines; Excitability; excitatory/inhibitory balance; Females; Homeostasis; Kainic acid; Males; Morphology; Pentylenetetrazole; Pyramidal cells; Receptors; RRID: SCR_003070; Seizures; Sex; SLC7A11; Spine; Substrates; xCT; γ-Aminobutyric acid A receptors
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.24971

System xc− (Sxc−) is a heteromeric antiporter (L‐cystine/L‐glutamate exchanger) expressed predominately on astrocytes in the central nervous system. Its activity contributes importantly to the maintenance of the ambient extracellular glutamate levels, as well as, to cellular redox homeostasis. Since alterations in glutamate levels and redox modifications could cause structural changes, we analyzed gross regional morphology of thionin‐stained brain sections and cellular and subcellular morphology of Golgi–Cox stained layer V pyramidal neurons in the primary motor cortex (PM1) of mice naturally null for SLC7A11 (SLC7A11sut/sut)—the gene that encodes the substrate specific light chain (xCT) for Sxc−. Intriguingly, in comparison to age‐ and sex‐matched wild‐type (SLC7A11+/+) littermate controls, we found morphologic changes—including increased dendritic complexity and mushroom spine area in males and reduced corpus callosum and soma size in females—that have previously been described, in each case, as morphological correlates of excitability. Consistent with this, we found that both male and female SLC7A11sut/sut mice had lower convulsive seizure thresholds and greater seizure severity than their sex‐matched wild‐type (SLC7A11+/+) littermates after acute challenge with two pharmacologically distinct chemoconvulsants: the Glu receptor agonist, kainic acid (KA), or the GABAA receptor antagonist, pentylenetetrazole (PTZ). These results suggest that the loss of Sxc− signaling in males and females perturbs excitatory/inhibitory (E/I) balance in vivo, potentially through its regulation of cellular and subcellular morphology. Male (M) and female (F) mice null for the cystine/glutamate antiporter, system xc−, have neuronal structural alterations including enhanced dendritic complexity (M), decreased soma size (F), and alterations in spine head widths (M,F). These cellular morphological alterations may explain the reduction in convulsive seizure threshold demonstrated in both sexes.