Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder

Abstract

IntroductionMajor depressive disorder (MDD) has a lifetime prevalence of 16% in the United States.1 Antidepressant drugs are the most used intervention for those with a diagnosis of depressive disorders, but the road to remission is long and uncertain, with 40% of patients never reaching full remission and at least 15% not experiencing any symptomatic improvements.2 Elucidating the biological bases of MDD is likely to provide novel targets for the development of more effective drugs, or at the very least, adjunctive treatments for existing antidepressants that increase the chance of remission.Speculation that norepinephrine plays a role in depressive disorders dates back to the early 1950s, and research since then increasingly supports this. The locus coeruleus (LC) in the pontine brainstem contains the cell bodies of the major source of norepinephrine in the brain and has been the subject of numerous investigations regarding the neuropathology of MDD.3 The human LC is an area with very high densities of radioligand binding of antidepressant drugs to monoamine oxidase, 4 the norepinephrine transporter 5 and the serotonin transporter.6 Numerous postmortem studies demonstrate abnormal neurochemistry of the noradrenergic LC in people with MDD and in people who died by suicide. A role of Background: Norepinephrine and glutamate are among several neurotransmitters implicated in the neuropathology of major depressive disorder (MDD). Glia deficits have also been demonstrated in people with MDD, and glia are critical modulators of central glutamatergic transmission. We studied glia in men with MDD in the region of the brain (locus coeruleus; LC) where noradrenergic neuronal cell bodies reside and receive glutamatergic input. Methods: The expression of 3 glutamate-related genes (SLC1A3, SLC1A2, GLUL) concentrated in glia and a glia gene (GFAP) were measured in postmortem tissues from men with MDD and from paired psychiatrically healthy controls. Initial gene expression analysis of RNA isolated from homogenized tissue (n = 9-10 pairs) containing the LC were followed by detailed analysis of gene expressions in astrocytes and oligodendrocytes (n = 6-7 pairs) laser captured from the LC region. We assessed protein changes in GFAP using immunohistochemistry and immunoblotting (n = 7-14 pairs). Results: Astrocytes, but not oligodendrocytes, demonstrated robust reductions in the expression of SLC1A3 and SLC1A2, whereas GLUL expression was unchanged. GFAP expression was lower in astrocytes, and we confirmed reduced GFAP protein in the LC using immunostaining methods. Limitations: Reduced expression of protein products of SLC1A3 and SLC1A2 could not be confirmed because of insufficient amounts of LC tissue for these assays. Whether gene expression abnormalities were associated with only MDD and not with suicide could not be confirmed because most of the decedents who had MDD died by suicide. Conclusion: Major depressive disorder is associated with unhealthy astrocytes in the noradrenergic LC, characterized here by a reduction in a...

Structural abnormality of the hippocampus associated with depressive symptoms in heart failure rats

“…Periaqueductal gray and pons, which are downstream targets of the hypothalamus, modulate cardiac sympathetic functions in rats (Farkas et al, 1998) and may be associated with aberrant sympathetic arousal in HF in combination with the hypothalamus (Triposkiadis et al, 2009). The number of astrocytes in amygdala, periaqueductal gray or pontine locus coeruleus is changed in acute or chronic stress or major depression (Sugama et al, 2011;Imbe et al, 2012;Chandley et al, 2013). A meta analysis of MRI studies revealed decrease in amygdala volume in unmedicated depressed individuals (Hamilton et al, 2008).…”

Functional DNA methylation in a transcript specific 3′UTR region of TrkB associates with suicide

“…13 Downregulation of this truncated TrkB transcript, in coordination with a network of several other astrocytic genes, 14 has been reported in several brain regions of suicide completers. 9 Interestingly, convergent evidence from studies investigating gene expression patterns 15 to studies focusing on cell morphology, 16 has been increasingly suggesting that astrocyte dysregulation plays an important role in depression and suicide.…”

TRH and TRH receptor system in the basolateral amygdala mediate stress-induced depression-like behaviors

“…In fact, stress-induced c-Fos induction is detected widely in the brain, although c-Fos induction levels vary across different brain regions (Kim and Han, 2006). The brain regions that are responding to stress and are potentially important for the regulation of mood states may include the prefrontal cortex (Mann et al, 2000;Arnsten, 2009), the nucleus accumbens (Russo and Nestler, 2013), the hippocampus (MacQueen et al, 2003), the amygdala (Maheu et al, 2013), the habenula (Li et al, 2013), the ventral tegmental area (Nestler and Carlezon, 2006), the locus coeruleus (Chandley et al, 2013), and dorsal raphe nuclei (Boldrini et al, 2008). Thus in an anatomical view, stress-and depression-related brain regions are diverse and related neural circuits appear to be complex.…”