Low Gene Expression of Excitatory Amino Acid Transporters in Astrocytes of the Locus Coeruleus From Subjects With Major Depressive Disorder

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Glutamate is a major stress-sensitive excitatory input to the noradrenergic locus coeruleus (LC) and pathology of both glutamatergic and noradrenergic systems is strongly implicated in major depressive disorder (MDD). Glutamatergic innervation of the LC originates in the frontal cortex and in local brainstem nuclei. Stress increases the release of glutamate in the LC which results in activation of noradrenergic LC neurons. Previous research has demonstrated abnormalities in the levels of glutamate receptor proteins and gene expressions in the postmortem LC of subjects with MDD as compared to normal control subjects providing further evidence for disruption of glutamate-norepinephrine communication in MDD. A principal mechanism for the termination of the action of neuronally-released glutamate is by reuptake via excitatory amino acid transporters (EAAT) located on glia, cells which express both EAAT1 and EAAT2. Here, the potential contribution of glia to glutamate pathology in the LC in MDD was studied by measuring gene expression of EAAT1 and EAAT2 in astrocytes captured from the immediate region of the postmortem LC from 6 pairs of subjects with MDD and psychiatrically normal control subjects. MDD and control subjects were carefully matched for age, RIN value (RNA integrity number), gender, cigarette smoking or non-smoking, and brain tissue pH. Laser capture microdissection was used to capture astrocytes from tissue sections labeled with a modified rapid GFAP-immunostaining, and gene expression levels were analyzed by quantitative PCR. Three reference genes were used as internal controls and the quality of the capture of astrocytes was confirmed by examining the gene expression of cell-type specific markers, including markers for noradrenergic neurons and oligodendrocytes. The gene expression of EAATs was significantly lower (EAAT1, -60%; p<0.001; EAAT2, -25%, P<0.01) in LC astrocytes from MDD subjects as compared to normal control subjects. To determine the regional specificity of these findings, gene expression levels of EAAT1 and EAAT2 were measured in homogenates of both gray and white matter from Brodmann’s area 10 of the cortex. No differences in EAAT gene expression in these cortical tissues were observed comparing MDD to control subjects. These findings indicate that disrupted glial transport of glutamate may contribute to altered glutamatergic transmission in the noradrenergic LC in MDD.

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