Title

Glutamate Receptor Gene Expression in Human Noradrenergic Neurons: Evidence of Altered Glutamate-Noradrenergic Signaling in Depression and Suicide

Document Type

Presentation

Publication Date

11-19-2008

Description

There is abundant evidence that both glutamatergic and noradrenergic transmission are disrupted in stress-related disorders such as major depressive disorder (MDD). Glutamate provides a major excitatory input to the noradrenergic locus coeruleus (LC), the primary source of norepinephrine in the brain. Stress increases glutamate activation of noradrenergic neurons in the LC. Glutamate signaling in the LC is mediated by several glutamate receptors expressed in the LC. Previous work from this laboratory has demonstrated elevated protein levels of the NMDA receptor subunit NR2C in the LC from MDD subjects compared to normal control subjects. Here, laser capture microdissection and quantitative gene expression analyses were used to evaluate the gene expression of selected glutamate receptors in noradrenergic neurons from the LC in postmortem brains from MDD subjects (n=6 males; 42±7 y) and psychiatrically normal control subjects (n=6 males; 42±7 y). No significant differences in brain pH, postmortem intervals, or RNA quality (estimated by RIN values) were observed between the two groups. None of the subjects had a diagnosis of a substance abuse disorder and none had a positive toxicological finding of antidepressant medication. Five of the 6 MDD subjects died by suicide. Gene expression levels were normalized using 3 reference genes and using cell number. The quality of the capture of pure populations of noradrenergic neurons was confirmed by examining gene expression of cell-type specific markers, including markers for glia. Gene expression levels of the NR2B and NR2C subunits of the NMDA receptor were robustly and significantly elevated in noradrenergic neurons collected from MDD subjects compared to control subjects. In contrast, gene expression levels of the AMPA receptor subunit GluR1, the metabotropic glutamate receptor mGluR5, as well as the reference genes actin, ubiquitin C, and GAPDH were not significantly different comparing MDD to control subjects. Altered glutamate receptor gene expression in noradrenergic neurons from MDD subjects provides evidence of abnormal glutamatergic control of noradrenergic neurotransmission in MDD.

This document is currently not available here.

Share

COinS