Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Karolewicz, Beata; Stockmeier, Craig A.; Ordway, Gregory A.

doi:10.1038/sj.npp.1300781

Cited by 71 publications

(54 citation statements)

References 62 publications

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“…Reduced uptake of glutamate by LC glia, as a result of reduced SLC1A3 and SLC1A2 expression, could directly contribute to altered glutamatergic signalling in the LC in people with MDD, as has been postulated previously. 14,15 However, the study by Bernard and colleagues 20 did not determine whether reduced levels of expression of glia-enriched genes were in fact isolated to glia, did not determine which type of glia was affected, and ultimately could not rule out the possibility that reduced glia gene expression was a result of a reduced number of glial cells in the LC region dissected for the gene expression studies. In the present study, we investigated the cellular source of altered glutamate transporter gene expression in the LC of people with MDD using postmortem brain tissues from people with characterized MDD and from psychiatrically healthy controls.…”

Section: Introductionmentioning

confidence: 99%

“…In the LC, equivalent rostrocaudal levels along the axis of the LC were obtained as previously described. 15 Tissue sections for laser capture microdissection (LCM) were prepared as described previously. 26 For Western blotting, frozen sections (50 µm) were cut, and tissue containing the LC was punch-dissected (10 punches isolated per tissue donor).…”

Section: Tissue Preparation and Sectioningmentioning

confidence: 99%

“…13 Furthermore, glutamatergic abnormalities in the postmortem LC of people with MDD, including elevated N-methyl-Daspartate receptor subunit expression and reduced neuronal nitric oxide synthase expression, have been observed. 14,15 A growing body of evidence shows a loss of glia or glia dysfunction in people with MDD; results have shown reduced glia, including oligodendrocytes and GFAP-labelled astrocytes, in cerebral cortical areas and the amygdala. [16][17][18][19] Since the actions of glutamate are terminated largely by its removal from the synaptic junction by the excitatory amino acid transporter 1 (EAAT1) and excitatory amino acid transporter 2 (EAAT2) found on glia, a reduction in glia or glia health could contribute to elevated glutamate in the brain.…”

Section: Introductionmentioning

confidence: 99%

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

Chandley

Szebeni

et al. 2013

J Psychiatry Neurosci

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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...

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Section: Introductionmentioning

confidence: 99%

Section: Tissue Preparation and Sectioningmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Chandley

Szebeni

et al. 2013

J Psychiatry Neurosci

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“…Although alterations in the density of monoaminergic receptors (reviewed in [31]) and subunits of the NMDA receptor [32,33] [48][49][50], required for further regulation of the extracellular concentrations of these neurotransmitters. Moreover, the ability of cultured astrocytes to take up serotonin can be blocked by fluoxetine or paroxetine [43,51], suggesting that glia along with neurons may participate in the therapeutic effects of these compounds in depression.…”

Section: Neurotransmitter Modulationmentioning

confidence: 99%

Gliogenesis and Glial Pathology in Depression

Rajkowska¹,

Miguel-Hidalgo²

2007

CNSNDDT

533

364

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Recent research has changed the perception of glia from being no more than silent supportive cells of neurons to being dynamic partners participating in brain metabolism and communication between neurons. This discovery of new glial functions coincides with growing evidence of the involvement of glia in the neuropathology of mood disorders. Unanticipated reductions in the density and number of glial cells are reported in fronto-limbic brain regions in major depression and bipolar illness. Moreover, age-dependent decreases in the density of glial fibrillary acidic protein (GFAP) -immunoreactive astrocytes and levels of GFAP protein are observed in the prefrontal cortex of younger depressed subjects. Since astrocytes participate in the uptake, metabolism and recycling of glutamate, we hypothesize that an astrocytic deficit may account for the alterations in glutamate/GABA neurotransmission in depression. Reductions in the density and ultrastructure of oligodendrocytes are also detected in the prefrontal cortex and amygdala in depression. Pathological changes in oligodendrocytes may be relevant to the disruption of white matter tracts in mood disorders reported by diffusion tensor imaging. Factors such as stress, excess of glucocorticoids, altered gene expression of neurotrophic factors and glial transporters, and changes in extracellular levels of neurotransmitters released by neurons may modify glial cell number and affect the neurophysiology of depression. Therefore, we will explore the role of these events in the possible alteration of glial number and activity, and the capacity of glia as a promising new target for therapeutic medications. Finally, we will consider the temporal relationship between glial and neuronal cell pathology in depression.Glial cells were first identified as non-neuronal elements in the nineteenth century by the anatomist R. Virchow (after [1]). At that time glia were thought to be no more than silent supportive "glue" for neurons and that glia were unable to participate in information processing. In the past two decades, research has changed this perception and provided evidence for glia being important dynamic partners of neuronal cells actively participating in brain metabolism, synaptic neurotransmission and communication between neurons [2]. The discovery of new glial functions coincides with growing evidence for the involvement of glia in the neuropathology of neurological [3] and more recently, psychiatric disorders, such as major depression and manic-depressive (bipolar) illness (reviewed in [4]) TYPES OF GLIAL CELLSGlia are the most numerous cells in the human brain, outnumbering neurons by a ratio of ten to one [5] (Fig. 1). This ratio drops to one-to-one in rodents [5,6] implying that increases in glia over neurons are associated with the progressive development of higher brain functions [7]. Although anecdotal, it is interesting that in the brain of Albert Einstein, the neuron/glia ratio in the associational parieto-temporal cortical area 39 was found to be smaller ...

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“…Recently, abnormalities in excitatory inputs (corticotropin releasing factor, glutamate) to the LC in depression and/or suicide have been reported [2,7,17,32]. It is reasonable to speculate that elevated LC activity in depression may be simultaneously associated with diminished inhibitory input to the LC.…”

Section: Introductionmentioning

confidence: 99%

Normal [3H]flunitrazepam binding to GABAA receptors in the locus coeruleus in major depression and suicide

Zhu¹,

Karolewicz²,

Nail³

et al. 2006

Brain Research

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Major depression and suicide are associated with altered concentrations of specific noradrenergic proteins in the human locus coeruleus (LC). Based on experimental studies that can reproduce these LC abnormalities in laboratory animals, we hypothesized that noradrenergic pathobiology in depression is a result of over-activity of the LC. LC activity is under the control of both excitatory and inhibitory inputs. A major inhibitory input to the LC is GABAergic, arising from the nucleus prepositus hypoglossi. Numerous studies demonstrating low levels of GABA in the CSF and plasma of subjects with major depressive disorder (MDD) raise the possibility that LC over-activity in depression may be secondary to reduced GABAergic input to the LC. Here, GABAergic input to the LC in depression was evaluated by studying the binding of [ 3 H]flunitrazepam to GABA A receptors at three anatomically-defined levels of the human postmortem LC. LC tissues were collected from subjects with MDD, subjects with depressive disorders including MDD that died as a result of suicide, and psychiatrically normal control subjects. A modest rostral-caudal gradient of GABA A receptor binding density was observed amongst all subjects. No significant differences in the amount of binding to GABA A receptors were observed between control subjects (n=21) and MDD subjects (n=9) or depressed suicide victims (n=17). These results demonstrate that GABA A receptor binding in the LC measured with [ 3 H]flunitrazepam is not altered in subjects with depressive illnesses.

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Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Cited by 71 publications

References 62 publications

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

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

Gliogenesis and Glial Pathology in Depression

Normal [3H]flunitrazepam binding to GABAA receptors in the locus coeruleus in major depression and suicide

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