An association between the reduced levels of SLC1A2 and GAD1 in the dorsolateral prefrontal cortex in major depressive disorder: possible involvement of an attenuated RAF/MEK/ERK signaling pathway

Abstract

Previous human postmortem studies have shown that expression of glutamate transporters (SLC1A2 and SLC1A3) and gamma-aminobutyric acid-synthesizing enzyme [glutamic acid decarboxylase 1 (GAD1)] are reduced in the dorsolateral prefrontal cortex (dlPFC) in subjects with major depressive disorder (MDD). However, no studies have explored the association between these two molecules and its related biological processes in MDD because of limited postmortem sample availability. Data sharing using the Stanley neuropathology consortium integrative database (SNCID), a web-based tool that integrates datasets from the same postmortem brain samples, allowed us to reanalyze existing postmortem data efficiently. We found two datasets where the mRNA levels of GAD1 and SLC1A2 in subregions of the dlPFC were significantly and marginally lower in subjects with MDD (n = 15) than in controls (n = 15) (p = 0.045 and 0.057, respectively). In addition, there was a positive correlation between these two molecules (n = 30, p < 0.05). Spearman's rank correlation analysis using all available datasets revealed that the expression levels of both GAD1 and SLC1A2 mRNAs were commonly correlated with the expression levels of several neuropathological markers in the dlPFC in all of the SNCID subjects (n = 60, p < 0.001). Most of these markers are known to be involved in the RAF/MEK/ERK signal transduction pathway. This exploratory study provides an initial step for future studies to investigate an association between the reductions in SLC1A2 and GAD1 mRNA expression and their relation to the attenuation of the RAF/MEK/ERK signaling pathway in the dlPFC in MDD. The integration of the existing archival data may shed light on one important aspect of the pathophysiology of MDD.