Major depression (MDD) is a chronic and debilitating mood disorder with a 16% lifetime prevalence 1
and is associated with excess mortality, especially from cardiovascular disease and through suicide 2
. Mood disorders, including MDD and bipolar disorder (BPD) are characterized by dysfunction of noradrenergic neurotransmission. Drugs that increase brain norepinephrine (NE)/serotonin (5-HT) levels act as antidepressants 3, 4
, whereas drugs that deplete NE/5-HT stores induce a depressive state 5, 6
. Currently, most antidepressant drugs directly or indirectly target 5-HT and/or NE systems of the brain, as these neurotransmitters have been suggested to be mechanistically relevant to the etiology of mood disorders 7
. However, drugs such as selective 5-HT reuptake inhibitors only produce remission in 37% of all patients, and if they show therapeutic responses, then only after 2-5 weeks 8
. These observations suggest that brain monoamine deficiency may be part of a much more complex pathogenesis of major depression that requires further investigation.
The locus coeruleus (LC), which is located in the rostral pontine tegmentum 9, 10
, possesses the largest number of NE-producing neurons in the mammalian brain. These neurons contain the pigment neuromelanin that gives the nucleus its characteristic dark color. LC neurons project widely throughout the entire central nervous system, including the cerebral cortex, thalamus, septum, hippocampus, hypothalamus, cerebellum, and spinal chord 11-13
. In addition there are intense reciprocal connections between LC and the 5-HT producing dorsal raphe neurons, which provide the basis for neurochemical communication between both monoamine systems 14
. With their wide-ranging and overlapping projections arising from the brainstem, both monoamine systems act in concert to modulate vigilance, sleep-wake cycle, memory, adaptive response to stress, and pain modulation 15
. These behaviors are disturbed in patients with MDD, and as a consequence their LC displays molecular abnormalities. Therefore, the current study focused on the locus coeruleus (LC) which synthesizes the majority of NE released in the forebrain 16
The study is an attempt to more clearly understand the biology of cells in the in the LC (neurons and glia) in depression.
Previous postmortem studies focused on the LC have shown increased protein levels of presynaptic alpha 2 adrenoreceptors in MDD, which inhibits the firing of LC neurons and subsequent norepinephrine secretion 17
. Protein levels of tyrosine hydroxylase, the rate limiting enzyme in the synthesis of norepinephrine, are likewise elevated in the LC of MDD patients 18
, whereas binding to norepinephrine transporter is reduced 19
. These results are consistent with the interpretation that: 1) noradrenergic neurotransmission is dysregulated in MDD, and 2) the LC represents a key region in the etiology of this disorder. The majority of post mortem studies involving the analysis of LC in MDD have focused on analyses of proteins involved in noradrenergic neurotransmission. Little is known, however, about mRNA expression, especially of non-adrenergic genes, in the LC of MDD patients.
Therefore, in the present study we used gene expression microarray technology in combination with laser-capture microdissection (LCM) to profile gene expression in the LC from post mortem brains of patients with MDD. These profiles were contrasted to those obtained from the LC of BPD patients and psychiatrically-normal subjects. Our approach yielded a number of candidate genes that may play a key role in the LC dysfunction in depression. Potentially altered gene transcripts were examined using quantitative real-time PCR (qPCR) and/or in situ
hybridization (ISH). The results implicate MDD-specific dysfunctions in glutamate and growth factor signaling with special emphasis on altered astroglial transcripts, which is in strong agreement with previous studies from dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (AnCg) of MDD patients 20, 21