Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression∗∗See accompanying Editorial, in this issue.

Rajkowska, Grażyna; Miguel-Hidalgo, José Javier; Wei, Jinrong; Dilley, Ginny E.; Pittman, Stephen D.; Meltzer, Herbert Y.; Overholser, James C.; Roth, Bryan L.; Stockmeier, Craig A.

doi:10.1016/s0006-3223(99)00041-4

Cited by 1,364 publications

(1,034 citation statements)

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“…On the other hand, several postmortem studies on major depression have given opposite findings, namely, prominent decrease in the number and the density of astrocytes in major depression patients compared to age‐matched nonpsychiatric controls. Such a reduction in astrocytic population was observed in the dorsolateral prefrontal (Cotter, Mackay, Landau, Kerwin, & Everall, 2001; Rajkowska et al., 1999), orbitofrontal (Rajkowska et al., 1999), subgenual (Ongur, Drevets, & Price, 1998), and anterior cingulate cortex (Cotter et al., 2001). This discrepancy may stem from a difference in brain regions studied.…”

Section: Discussionmentioning

confidence: 99%

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test

et al. 2018

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IntroductionRecent studies imply that glial activation plays a role in the pathogenesis of psychiatric disorders, such as schizophrenia and major depression. We previously demonstrated that Gunn rats with hyperbilirubinemia show congenital gliosis and schizophrenia‐like behavior.MethodsAs it has been suggested that major depression involves glial activation associated with neuroinflammation, we examined whether Gunn rats show depression‐like behavior using the forced swimming test (FST) and the tail suspension test (TST). In addition, we quantitatively evaluated both microgliosis and astrogliosis in the hippocampus of Gunn rats using immunohistochemistry analysis of the microglial marker ionized calcium‐binding adaptor molecule (Iba) 1 and the astrocytic marker S100B.ResultsBoth the FST and TST showed that immobility time of Gunn rats was significantly longer than that of normal control Wistar rats, indicating that Gunn rats are somewhat helpless, a sign of depression‐like behavior. In the quantification of immunohistochemical analysis, Iba1immunoreactivity in the dentate gyrus (DG), cornu ammonis (CA) 1, and CA3 and the number of Iba1‐positive cells in the CA1 and CA3 were significantly increased in Gunn rats compared to Wistar rats. S100B immunoreactivity in the DG, CA1, and CA3 and the number of S100B‐positive cells in the DG and CA3 were significantly increased in Gunn rats compared to Wistar rats.ConclusionOur findings suggest that both microglia and astrocyte are activated in Gunn rats and their learned helplessness could be related to glial activation.

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Section: Discussionmentioning

confidence: 99%

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test

et al. 2018

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“…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%

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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“…Moreover, since studies have shown that increased expression of ER stress proteins prevents Ca 2 ϩ depletion from the ER and protects against cellular damage and death (Lievremont et al 1997;Liu et al 1997Liu et al , 1998Yu et al 1999), it is possible that an elevation of these proteins in this subgroup of patients may have been an attempt to compen-sate for these neuropathologic changes in this patient group. Indeed, several recent studies are suggestive of cellular loss and glial changes in cortical regions of patients with MDD, which may be correlated with severity of illness (Ongur et al 1998;Rajkowska et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Increased Temporal Cortex ER Stress Proteins in Depressed Subjects Who Died by Suicide

Bown

Wang

MacQueen

et al. 2000

Neuropsychopharmacology

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Regulation of ER stress proteins, such as the 78-kilodalton glucose regulated protein (GRP78) by chronic treatment with mood stabilizing drugs suggests that this family of proteins may be involved in the pathophysiology of mood disorders. Indeed, increased levels of GRP78, GRP94, and calreticulin, a third member of the ERCurrent theories of the pathophysiology of mood disorders suggest that prolonged increases in glucocorticoid levels, likely the result of prolonged environmental stress, lead to biochemical changes in cortical and limbic neurons that leave individuals vulnerable to depression (Duman et al. 1997). A number of studies have found evidence of neuronal atrophy and loss of hippocampal neurons in response to stress (Magarinos et al. 1996;Uno et al. 1989;Sapolsky et al. 1985), and a report of reduced hippocampal volumes in elderly patients with histories of depression suggests that analogous processes may occur in individuals with depression (Sheline et al. 1996). Some models of mood disorders (Hyman and Nestler 1996; Post 1992) have attempted to incorporate the notion of compensatory processes into an understanding of the pathophysiologic changes that occur in patients with mood disorders, but few studies have tested these notions empirically (Post 1992). Part of the difficulty has been identifying neuroprotective mechanisms that may be of relevance for mood disorders.Recently, we found that treatment with the mood stabilizing drugs, valproate and carbamazepine, increased expression of the 78-kilodalton glucose-regulated protein (GRP78) . GRP78 is a member of the ER stress protein family that includes GRP94 and calreticulin, all of which function as Ca 2 ϩ binding proteins and molecular chaperones to assist in the regulation of protein folding (Gething 1997). These proteins have neuroprotective properties, are induced by seizures and ischemic damage, and may be involved in Alzheimer's disease pathology (Yu et al. 1999;Lowenstein et al. 1994;Hamos et al. 1991).Increased expression of ER stress proteins by mood stabilizing drugs suggest that these proteins may be in- METHODS Postmortem brain tissue was obtained from the StanleyFoundation Neuropathology Consortium (4 groups of n ϭ 15 age-and sex-matched subjects, i.e., subjects with bipolar disorder (BD), subjects with Major Depressive Disorder (MDD), subjects with schizophrenia (SCZ), and non-psychiatric, non-neurologic comparison subjects) (Johnston et al. 1997). Details on dissection and clinical characteristics have been previously published (Dowlatshahi et al. 1998(Dowlatshahi et al. , 1999. Briefly, all medical records for psychiatric cases were reviewed by two psychiatrists. Diagnosis was determined according to DSM-IV criteria. If there was disagreement about the diagnosis, a third psychiatrist read the records. If a diagnosis could not be established, a family member was then interviewed. All interviewed relatives were first degree except for two (one aunt and one father-in-law). Similarly, a clinical interview was performed with a family member...

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Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression∗∗See accompanying Editorial, in this issue.

Cited by 1,364 publications

References 43 publications

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test

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

Increased Temporal Cortex ER Stress Proteins in Depressed Subjects Who Died by Suicide

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