A bioinformatic inquiry of the EAAT2 interactome in postmortem and neuropsychiatric datasets

Altered expression and localization of the glutamate transporter EAAT2 is found in schizophrenia and other neuropsychiatric (major depression, MDD) and neurological disorders (amyotrophic lateral sclerosis, ALS). However, the EAAT2 interactome, the network of proteins that physically or functionally interact with EAAT2 to support its activity, has yet to be characterized in severe mental illness. We compiled a list of "core" EAAT2 interacting proteins. Using Kaleidoscope, an R-shiny application, we data mined publically available postmortem transcriptome datasets to determine whether components of the EAAT2 interactome are differentially expressed in schizophrenia and, using Reactome, identify which interactome-associated biological pathways are altered. Overall, these "look up" studies highlight region-specific, primarily frontal cortex (dorsolateral prefrontal cortex and anterior cingulate cortex), changes in the EAAT2 interactome and implicate altered metabolism pathways in schizophrenia. Pathway analyses also suggest that perturbation of components of the EAAT2 interactome in animal models of antipsychotic administration impact metabolism. Similar changes in metabolism pathways are seen in ALS, in addition to altered expression of many components of the EAAT2 interactome. However, although EAAT2 expression is altered in a postmortem MDD dataset, few other components of the EAAT2 interactome are changed. Thus, "look up" studies suggest region- and disease-relevant biological pathways related to the EAAT2 interactome that implicate glutamate reuptake perturbations in schizophrenia, while providing a useful tool to exploit "omics" datasets.