Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder

Rajkowska, Grażyna; Halaris, Angelos; Selemon, Lynn D.

doi:10.1016/s0006-3223(01)01080-0

Cited by 524 publications

(379 citation statements)

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“…Several postmortem brain studies also suggest reductions in cell number and in density and size of cortical and hippocampal neurons (Rajkowska, 1997(Rajkowska, , 2000Benes et al, 1998;Rajkowska et al, 1999Rajkowska et al, , 2001. Altered brain structures have also been demonstrated in brain of suicide subjects (Altschuler et al, 1990;Rajkowska, 1997;Rajkowska et al, 2001). In addition, synaptic loss has been correlated with the cognitive disturbances associated with mood disorders (Duman, 2002;Fossati et al, 2004;Kolomeets et al, 2005).…”

Section: Discussionmentioning

confidence: 98%

“…A number of studies suggest that subjects with affective disorders show morphological changes in the brain, including atrophy of neurons and reduction in volumes of PFC and hippocampus (Sheline et al, 1996;Drevets et al, 1997Drevets et al, , 1999Bremner et al, 2000). Several postmortem brain studies also suggest reductions in cell number and in density and size of cortical and hippocampal neurons (Rajkowska, 1997(Rajkowska, , 2000Benes et al, 1998;Rajkowska et al, 1999Rajkowska et al, , 2001. Altered brain structures have also been demonstrated in brain of suicide subjects (Altschuler et al, 1990;Rajkowska, 1997;Rajkowska et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Dwivedi

Rizavi

Teppen

et al. 2007

Neuropsychopharmacol

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Phosphoinositide 3 (PI 3)-kinase is one of the key signaling enzymes that participates in a myriad of physiological functions in brain and is utilized by neurotrophins to mediate neuronal plasticity, cell survival, and inhibition of apoptosis for several neuronal subtypes. Our recent demonstration that expression of neurotrophic factors and activation of the receptor tyrosine kinase B are significantly altered in postmortem brain of suicide subjects led us to examine whether suicide brain is associated with alterations in PI 3-kinase signaling. In prefrontal cortex (PFC), hippocampus, and cerebellum of suicide (n ¼ 28) and nonpsychiatric control (n ¼ 21) subjects we examined catalytic activation of PI 3-kinase, and mRNA and protein levels of regulatory (p85a, p85b) and catalytic (p110a, p110b) subunits of PI 3-kinase. It was observed that the catalytic activity of PI 3-kinase was significantly reduced in PFC and hippocampus of suicide subjects compared with nonpsychiatric control subjects. Competitive PCR analysis revealed significantly reduced mRNA expression of p85b and p110a and increased expression of p85a subunit isoforms in PFC and hippocampus of suicide subjects. Alterations in these catalytic and regulatory subunits were accompanied by changes in their respective protein levels. These changes were not present in cerebellum of suicide subjects. Also, these changes were present in all suicide subjects irrespective of psychiatric diagnosis. Our findings of reduced activation and altered expression of specific PI 3-kinase regulatory and catalytic subunit isoforms demonstrate abnormalities in this signaling pathway in postmortem brain of suicide subjects and suggest possible involvement of aberrant PI 3-kinase signaling in the pathogenic mechanisms of suicide.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Dwivedi

Rizavi

Teppen

et al. 2007

Neuropsychopharmacol

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“…Glial cell reductions in mood disorders have also been reported in other areas of frontal cortex, such as: orbital prefrontal cortex (Rajkowska et al, 1999), subgenual cortex (Ongur et al, 1998), and anterior cingulate cortex (Cotter et al, 2001). In MDD, these reductions in glial cells appear to be more consistent and of a larger magnitude than the pathology of neuronal cells (Cotter et al, 2002b;Cotter et al, 2001;Ongur et al, 1998;Rajkowska et al, 1999Rajkowska et al, , 2001.…”

Section: Introductionmentioning

confidence: 84%

“…In MDD, a significant decrease in the density of Nissl-stained glial cells is observed within layers III and V of the dorsolateral prefrontal cortex (dlPFC, Brodmann area 9), as compared to psychiatrically normal age-matched control subjects (Cotter et al, 2002a;Rajkowska et al, 1999). In bipolar disorder, reductions in glial cell density are reported in deep layer III (Rajkowska et al, 2001). Glial cell reductions in mood disorders have also been reported in other areas of frontal cortex, such as: orbital prefrontal cortex (Rajkowska et al, 1999), subgenual cortex (Ongur et al, 1998), and anterior cingulate cortex (Cotter et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Age-Dependent Reductions in the Level of Glial Fibrillary Acidic Protein in the Prefrontal Cortex in Major Depression

Miguel-Hidalgo

O'Dwyer

et al. 2004

Neuropsychopharmacol

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233

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The density of glial cells is reduced in certain layers of the dorsolateral prefrontal cortex in major depressive disorder (MDD). Moreover, there are reductions in the packing density of glial fibrillary acidic protein (GFAP) immunoreactive astrocytes in the same cortical layers in younger subjects with MDD. The objective of the present study was to test if the level of GFAP is preferentially decreased in younger subjects with MDD, and whether GFAP levels are correlated with the age of onset of depression. Post-mortem brain tissue punches from dorsolateral prefrontal cortex were collected from 15 subjects with MDD and 15 age-matched psychiatrically normal control subjects. Western blots were performed on gels containing duplicated samples from both subjects of each matched pair, and on gels containing samples at different ages from either the MDD or the control group. The GFAP level was calculated as the ratio of the optical density of GFAP bands to actin bands in subjects with MDD and nonpsychiatric controls. Levels of GFAP were significantly lower in subjects with MDD as compared to controls and this decrease was most prominent in subjects less than 60 years old at the time of death. In the MDD group, GFAP levels were positively correlated with age at the time of death and show a trend toward correlation with the age of onset of depression. These findings indicate that a decrease in levels of GFAP may contribute to the pathophysiology of MDD, particularly in subjects of relatively young age.

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“…[170][171][172][173][174] Although some reports did not differentiate between the loss of microglial cells or astrocytes, this difference is crucial due to the different effects of the type 1/type 2 immune response. Recent studies show that in particular astrocytes are diminished in MD, [175][176][177] although the data are not fully consistent.…”

Section: Astrocytes Microglia and Type 1/type 2 Responsementioning

confidence: 99%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

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Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder

Cited by 524 publications

References 47 publications

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Age-Dependent Reductions in the Level of Glial Fibrillary Acidic Protein in the Prefrontal Cortex in Major Depression

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

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