Fibrillary astrocytes are decreased in the subgenual cingulate in schizophrenia

Decreases in astrocyte density and in glial fibrillary acid protein (GFAP) mRNA in the anterior cingulate cortex have been reported changed in mood and affective disorders. Our study examines the relative density and frequency of fibrillary and gemistocytic astrocytes in the white matter of the subgenual cingulate cortex in 11 schizophrenia, 16 bipolar disorder, 20 major depression and 20 normal control cases. Serial coronal sections were stained with H&E for anatomical guidance and GFAP immunohistochemistry for astrocyte identification. Astrocyte density was measured using systematic anatomical distinctions and randomised counting methods previously reported. Astrocytes were classified as fibrillary or gemistocytic based on staining and morphometric criteria and were measured in the crown and base of the gyral white matter. Fibrillary astrocytes were decreased in the base of the cingulate white matter in schizophrenia (p = 0.046), with no change in the density of gemistocytic astrocytes. There was no change in density of gemistocytic astrocytes. This suggests that the previously reported decrease in astrocytes in schizophrenia in the subgenual cingulate is accounted for only by a change in fibrillary astrocytes. With recent findings suggesting fibrillary astrocytes regulate synaptic glutamate this morphological change may relate to disregulation of function of the subgenual cingulate cortex.     

Shape differences in the corpus callosum in first-episode schizophrenia and first-episode psychotic affective disorder

OBJECTIVE: The corpus callosum, the largest white matter tract in the brain, is a midline structure associated with the formation of the hippocampus, septum pellucidum, and cingulate cortex, which have been implicated in the pathogenesis of schizophrenia. Corpus callosum shape deformation, therefore, may reflect a midline neurodevelopmental abnormality. METHOD: Corpus callosum area and shape were analyzed in 14 first-episode psychotic patients with schizophrenia, 19 first-episode psychotic patients with affective disorder, and 18 normal comparison subjects. RESULTS: No statistically significant corpus callosum area differences between groups were found, but there were differences in the structure's shape between the patients with schizophrenia and the comparison subjects. A correlation between width and angle of the corpus callosum was found in patients with affective disorder. CONCLUSIONS: Corpus callosum shape abnormalities in first-episode psychotic patients with schizophrenia may reflect a midline neurodevelopmental abnormality.     

Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder

Background

Brain imaging studies suggest that volume reductions and compromised white matter integrity occur in schizophrenia and bipolar disorder (BD). However, the cellular correlates have not yet been identified. To address this issue we assessed oligodendrocyte, astrocyte and microglial populations in postmortem white matter from schizophrenia, BD and nonpsychiatric control samples.

Methods

The density, areal fraction and spatial distribution of glial fibrillary acidic protein (GFAP)-expressing astrocytes and ionized calcium-binding adaptor molecule-1 (IBA-1)-expressing microglia as well as the density, nuclear size and spatial distribution of Nissl-stained oligodendrocytes were quantified in postmortem white matter adjacent to the dorsolateral prefrontal cortex (Brodmann area 9) in schizophrenia, BD and control samples (n = 20). In addition, the oligodendrocyte-associated proteins myelin basic protein and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) were quantified in the same samples by enzyme-linked immunosorbent assay and immunoblotting.

Results

Oligodendrocyte density (p = 0.012) and CNPase protein levels (p = 0.038) differed between groups, being increased in BD compared with control samples. The GFAP area fraction (p = 0.05) and astrocyte spatial distribution (p = 0.040) also differed between groups, reflecting decreased area fraction and increased cell clustering in both schizophrenia and BD samples.

Limitations

Oligodendrocytes were identified using morphological criteria.

Conclusion

This study provides evidence for glial pathology in prefrontal white matter in schizophrenia and BD. Changes in oligodendrocyte and astrocyte populations in white matter in the major psychiatric disorders may reflect disruptions in structural or metabolic support of axons.     

Expression of CB<Subscript>1</Subscript> cannabinoid receptor in the anterior cingulate cortex in schizophrenia,bipolar disorder,and major depression

Summary The human endogenous cannabinoid system is an appealing target in the investigation of psychiatric disorders. In schizophrenia, endocannabinoids and their receptors are involved in the pathology of the disease. Previous studies reported an increased radioligand binding to cannabinoid receptors 1 (CB₁) in schizophrenia, both in the dorsolateral prefrontal cortex and in the anterior cingulate cortex (ACC). We analyzed the expression of the CB₁ receptors in the ACC at the protein level using immunohistochemistry. In a quantitative postmortem study, 60 patients suffering from schizophrenia, bipolar disorder, major depression and controls were included. Numerical densities of neurons and glial cells immunopositive for CB₁ receptors were evaluated. No evidence of an increased or decreased density of CB₁ receptor immunopositive cells in schizophrenia or bipolar disorder was found. In major depression, CB₁ receptor immunopositive glial cells in the grey matter were decreased. Furthermore, our data show that different medications have an impact on the expression of CB₁ receptors in the ACC.     

Preliminary evidence of within-subject changes in gray matter density associated with remission of bipolar depression

A preliminary within-subjects MRI study of seven patients with a diagnosis of bipolar I disorder revealed that, compared to remission, depression was associated with gray matter density increases in subgenual prefrontal cortex, parahippocampal gyrus, and inferior temporal gyri. Decreases were observed in superior and inferior frontal gyri and anterior cingulate.     

Subgenual cingulate cortex volume in first-episode psychosis.

OBJECTIVE: Gray matter volume and glucose utilization have been reported to be reduced in the left subgenual cingulate of subjects with familial bipolar or unipolar depression. It is unclear whether these findings are secondary to recurrent illness or are part of a familial/genetic syndrome. The authors' goal was to clarify these findings. METHOD: Volumetric analyses were performed by using magnetic resonance imaging in 41 patients experiencing their first episode of affective disorder or schizophrenia and in 20 normal comparison subjects. RESULTS: The left subgenual cingulate volume of the patients with affective disorder who had a family history of affective disorder was smaller than that of patients with affective disorder with no family history of the illness and the normal comparison subjects. Patients with schizophrenia did not differ from comparison subjects in left subgenual cingulate volume. CONCLUSIONS: Left subgenual cingulate abnormalities are present at first hospitalization for psychotic affective disorder in patients who have a family history of affective disorder.     

Subgenual prefrontal cortex volumes in major depressive disorder and schizophrenia: diagnostic specificity and prognostic implications

OBJECTIVE: A variety of findings have implicated the portion of the anterior cingulate cortex ventral to the corpus callosum in the pathophysiology of familial depressive disorder. There are, as yet, few data to address the specificity of these abnormalities to depressive disorders or to characterize their stability over time. METHOD: The authors studied 10 subjects who were judged to have had major depressive disorder with psychotic features, who underwent magnetic resonance imaging (MRI) protocols, and who participated in a longitudinal study of recent-onset psychosis. These were group-matched to 10 subjects with schizophrenia and to 10 well comparison subjects. Volumetric measures were made of the posterior and anterior portions of the subgenual prefrontal cortex for these 30 subjects. Follow-up scans done an average of 4 years after intake were available for seven subjects with major depressive disorder, nine subjects with schizophrenia, and five well comparison subjects. RESULTS: Volumes of the left side of the posterior subgenual prefrontal cortex differed significantly by group and were smallest for the group with psychotic major depressive disorder. Volumes of the anterior subgenual prefrontal cortex did not differ significantly by group. Patients with major depressive disorder were more likely to show increases in posterior subgenual prefrontal cortex volume on follow-up than were comparison subjects or patients with schizophrenia. CONCLUSIONS: These findings add to the evidence that abnormalities in the subgenual region of the anterior cingulate play a role in at least some types of mood disorder.     

Neuropathological changes in the nucleus basalis in schizophrenia

The nucleus basalis has not been examined in detail in severe mental illness. Several studies have demonstrated decreases in glia and glial markers in the cerebral cortex in schizophrenia, familial bipolar disorder and recurrent depression. Changes in neocortical neuron size and shape have also been reported. The nucleus basalis is a collection of large cholinergic neurons in the basal forebrain receiving information from the midbrain and limbic system, projecting to the cortex and involved with attention, learning and memory, and receives regulation from serotonergic inputs. Forty-one cases aged 41–60 years with schizophrenia or major depressive disorder with age-matched controls were collected. Formalin-fixed paraffin-embedded coronal nucleus basalis sections were histologically stained for oligodendrocyte identification with cresyl-haematoxylin counterstain, for neuroarchitecture with differentiated cresyl violet stain and astrocytes were detected by glial fibrillary acid protein immunohistochemistry. Cell density and neuroarchitecture were measured using Image Pro Plus. There were larger NB oval neuron soma in the combined schizophrenia and major depression disorder groups (p = 0.038), with no significant change between controls and schizophrenia and major depression disorder separately. There is a significant reduction in oligodendrocyte density (p = 0.038) in the nucleus basalis in schizophrenia. The ratio of gemistocytic to fibrillary astrocytes showed a greater proportion of the former in schizophrenia (18.1 %) and major depressive disorder (39.9 %) than in controls (7.9 %). These results suggest glial cell abnormalities in the nucleus basalis in schizophrenia possibly leading to cortical-limbic disturbance and subcortical dysfunction.     

Immunohistochemical Localization of Phosphorylated Glial Fibrillary Acidic Protein in the Prefrontal Cortex and Hippocampus from Patients with Schizophrenia, Bipolar Disorder, and Depression

Increasingly, abnormalities of glial cell function have been implicated in pathological studies of the major mental illnesses (schizophrenia, bipolar disorder, and major depression). In a recent proteomic study, four isoforms of astrocytic glial fibrillary acidic protein (GFAP) were decreased in one or more of these diseases. In the current study, we sought to determine the immunohistochemical localization of phosphorylated GFAP (pGFAP) in the prefrontal cortex and hippocampus and to describe possible disease-related changes in the distribution of pGFAP containing astrocytes. In the prefrontal cortex, interlaminar astrocytes in layer I and stellate astrocytes in layers II and VI were labeled. Labeled cells were also present adjacent to blood vessels in the gyral white matter and in underlying white matter generally. In the hippocampus, labeled cells were present in the polymorphic layer of the dentate gyrus. In the prefrontal cortex, schizophrenia and major depression were characterized by decreased labeling of astrocytes adjacent to blood vessels. There were no significant differences between the diagnostic groups in the other prefrontal layers or in the hippocampus. These results suggest that reduced numbers or functional regulation of pGFAP containing astrocytes occurs in schizophrenia and major depression. The mechanism by which this deficit occurs is not known, but it may adversely effect the regulation of neuronal metabolism, communication, and response to injury.     

Anterior cingulate cortex pathology in schizophrenia and bipolar disorder

To explore possible morphological abnormalities in the dorsal and subgenual parts of anterior cingulate cortex in mood disorders and schizophrenia, we performed a quantitative postmortem study of 44 schizophrenic patients, 21 patients with sporadic bipolar disorder, 20 patients with sporadic major depression, and 55 age- and sex-matched control cases. All individuals were drug na?ve or had received psychotropic medication for less than 6 months, and had no history of substance abuse. Neuron densities and size were estimated on cresyl violet-stained sections using a stereological counting approach. The distribution and density of microtubule-associated (MAP2, MAP1b) and tau proteins were assessed by immunocytochemistry and quantitative immunodot assay. Mean total and laminar cortical thicknesses as well as mean pyramidal neuron size were significantly decreased in the dorsal and subgenual parts of areas 24 (24sg) in schizophrenic cases. Patients with bipolar disorder showed a substantial decrease in laminar thickness and neuron densities in layers III, V, and VI of the subgenual part of area 24, whereas patients with major depression were comparable to controls. Immunodot assay showed a significant decrease of both MAP2 and MAP1b proteins in bipolar patients but not in patients with schizophrenia and major depression. The neuroanatomical and functional significance of these findings are discussed in the light of current hypotheses regarding the role of areas 24 and 24sg in schizophrenia and bipolar disorder.     

Combined analysis of grey matter voxel-based morphometry and white matter tract-based spatial statistics in late-life bipolar disorder

Background

Previous magnetic resonance imaging (MRI) studies in young patients with bipolar disorder indicated the presence of grey matter concentration changes as well as microstructural alterations in white matter in various neocortical areas and the corpus callosum. Whether these structural changes are also present in elderly patients with bipolar disorder with long-lasting clinical evolution remains unclear.

Methods

We performed a prospective MRI study of consecutive elderly, euthymic patients with bipolar disorder and healthy, elderly controls. We conducted a voxel-based morphometry (VBM) analysis and a tract-based spatial statistics (TBSS) analysis to assess fractional anisotropy and longitudinal, radial and mean diffusivity derived by diffusion tensor imaging (DTI).

Results

We included 19 patients with bipolar disorder and 47 controls in our study. Fractional anisotropy was the most sensitive DTI marker and decreased significantly in the ventral part of the corpus callosum in patients with bipolar disorder. Longitudinal, radial and mean diffusivity showed no significant between-group differences. Grey matter concentration was reduced in patients with bipolar disorder in the right anterior insula, head of the caudate nucleus, nucleus accumbens, ventral putamen and frontal orbital cortex. Conversely, there was no grey matter concentration or fractional anisotropy increase in any brain region in patients with bipolar disorder compared with controls.

Limitations

The major limitation of our study is the small number of patients with bipolar disorder.

Conclusion

Our data document the concomitant presence of grey matter concentration decreases in the anterior limbic areas and the reduced fibre tract coherence in the corpus callosum of elderly patients with long-lasting bipolar disorder.     

Regional Heterogeneity of Cuprizone-Induced Demyelination: Topographical Aspects of the Midline of the Corpus Callosum

The cuprizone model is a suitable animal model of de- and remyelination secondary to toxin-induced oligodendrogliopathy. From a pharmaceutical point of view, the cuprizone model is a valuable tool to study the potency of compounds which interfere with toxin-induced oligodendrocyte cell death or boost/inhibit remyelinating pathways and processes. The aim of this study was to analyze the vulnerability of neighboring white mater tracts (i.e., the fornix and cingulum) next to the midline of the corpus callosum which is the region of interest of most studies using this model. Male mice were fed cuprizone for various time periods. Different white matter areas were analyzed for myelin (anti-PLP), microglia (anti-IBA1), and astrocyte (anti-GFAP) responses by means of immunohistochemistry. Furthermore, Luxol fast blue–periodic acid Schiff stains were performed to validate loss of myelin-reactive fibers in the different regions. Cuprizone induced profound demyelination of the midline of the corpus callosum and medial parts of the cingulum that was paralleled by a significant astrocyte and microglia response. In contrast, lateral parts of the corpus callosum and the cingulum, as well as the fornix region which is just beneath the midline of the corpus callosum appeared to be resistant to cuprizone exposure. Furthermore, resistant areas displayed reduced astrogliosis and microgliosis. This study clearly demonstrates that neighboring white matter tracts display distinct vulnerability to toxin-induced demyelination. This important finding has direct relevance for evaluation strategies in this frequently used animal model for multiple sclerosis.     

Changes in cortical thickness in the frontal lobes in schizophrenia are a result of thinning of pyramidal cell layers

Decreased cortical thickness and reduced activity as measured by fMRI in the grey matter of the subgenual cingulate cortex have been reported in schizophrenia and bipolar disorder, and cortical grey matter loss has been reliably reported in the frontal and temporal lobes in schizophrenia. The aim of this study was to examine the thickness of each of the six cortical layers in the subgenual cingulate cortex, five frontal lobe and four temporal lobe gyri. We examined two separate cohorts. Cohort 1 examines the subgenual cingulate cortex (SCC) in schizophrenia (n = 10), bipolar disorder (n = 15) and major depressive disorder (n = 20) against control subjects (n = 19). Cohort two examines frontal and temporal gyri in schizophrenia (n = 16), major depressive disorder (n = 6) against matched controls (n = 32). The cohorts were selected with identical clinical criteria, but underwent different tissue processing to contrast the effect of chemical treatment on tissue shrinkage. Measurements of layer I-VI thickness were taken from cresyl-violet- and haematoxylin-stained sections in cohort one and from cresyl-violet- and H&E-stained sections in cohort two. SCC cortical thickness decreased in male subjects with bipolar disorder (p = 0.048), and male schizophrenia cases showed a specific decrease in the absolute thickness of layer V (p = 0.003). Compared to controls, the relative thickness of layer V in the crown of the SCC decreased in schizophrenia (p < 0.001). A significant decrease in total cortical thickness was observed across the frontal lobe in schizophrenia (p < 0.0001), with specific pyramidal layer thinning in layers III (p = 0.0001) and V (p = 0.005). There was no effect of lateralization. No changes were noted in temporal lobe cortical thickness. This study demonstrates diminished pyramidal layer thickness resulting in decreased frontal lobe thickness in schizophrenia.     

Glial Cell Lineages in the Rat Cerebral Cortex

I have traced the fates of glial cell progenitors in the rat cerebral cortex marked with a recombinant retrovirus throughout most of the period of corticogenesis, from embryonic (E) day 14 to postnatal (P) day 14. Discrete clusters of clonally related glia were examined in serially cut sections, and their phenotypes identified using reliable light and electron microscopic criteria. Analysis of a large number of clones marked with retrovirus at various stages of embryonic life contained, with very few exceptions, either all astrocytes or all oligodendrocytes. This observation suggests that the ventricular zone contains separate progenitor cells for the two glial cell types. Oligodendrocyte clones were rarely seen in the cortices injected with retrovirus at the early stages of corticogenesis (E14-E16), suggesting that there is a very small number of oligodendrocyte progenitors in the ventricular zone at these early stages. Their frequency increased significantly at later embryonic ages. At these later stages, ventricular zone cells also give rise to progenitor cells that make up the subventricular zone in early postnatal life. Injections of retrovirus in this proliferative zone shortly after birth resulted in the generation of labeled astrocyte and oligodendrocyte clones in the cortical gray and white matter, with the astrocyte clones being in the majority. Injections at increasingly later stages resulted in the presence, predominantly in the white matter of both hemispheres and in the corpus callosum, of progressively more oligodendrocyte clones and fewer astrocyte clones. Injections at P14 generated only oligodendrocyte clones in the white matter of both hemispheres. A small number of clusters (<10%) generated after subventricular zone injections contained both astrocytes and oligodendrocytes, suggesting that single subventricular zone cells can differentiate into both glial cell types.     

Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder

BACKGROUND: Glial cells are more numerous than neurons in the cortex and are crucial to neuronal function. There is evidence for reduced neuronal size in schizophrenia, with suggestive evidence for reduced glial cell density in mood disorders. In this investigation, we have simultaneously assessed glial cell density and neuronal density and size in the anterior cingulate cortex in schizophrenia, major depressive disorder, and bipolar disorder. METHODS: We examined tissue from area 24b of the supracallosal anterior cingulate cortex in 60 postmortem brain specimens from 4 groups of 15 subjects, as follows: major depressive disorder, schizophrenia, bipolar disorder, and normal controls. Glial cell density and neuronal size and density were examined in all subjects using the nucleator and the optical disector. RESULTS: Glial cell density (22%) (P =.004) and neuronal size (23%) (P =.01) were reduced in layer 6 in major depressive disorder compared with controls. There was some evidence for reduced glial density in layer 6 (20%) (P =.02) in schizophrenia compared with controls, before adjusting for multiple layerwise comparisons, but there were no significant changes in neuronal size. There was no evidence for differences in glial density or neuronal size in bipolar disorder compared with controls. Neuronal density was similar in all groups to that found in controls. CONCLUSION: These findings suggest that there is reduced frontal cortical glial cell density and neuronal size in major depressive disorder.     

Changes in region- and cell type-specific expression patterns of neutral amino acid transporter 1 (ASCT-1) in the anterior cingulate cortex and hippocampus in schizophrenia,bipolar disorder and major depression

Summary. Although, the pathogenetic mechanisms of schizophrenia, bipolar disorder, and major depression are not clearly understood, various neurotransmitter systems are reported to have altered expression patterns of their receptor and transporter proteins. Changes in the expression of the neutral amino acid transporter 1 (ASCT-1) protein in the anterior cingulate gyrus and the hippocampus were investigated using immunohistochemistry and western blotting. A significant decrease in ASCT-1 immunoreactivity in neurons in the cingulate cortex as well as astrocytes of the white matter was seen in schizophrenia. In bipolar disorder and major depression, similar results were seen for neurons. In the hippocampus, there was a striking loss of immunoreactivity on astrocytes, neurons and interneurons in multiple regions in schizophrenia and bipolar disorder, while only minor changes were seen in major depression. The altered expression of ASCT-1 in neurons and astrocytes reflects profound changes in glutamatergic neurotransmission and highlights a significant role of astrocytes in the pathophysiology of neurotransmission in these major psychiatric disorders.     

Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression, but not schizophrenia

Glial fibrillary acidic protein (GFAP) is a major protein of astrocyte intermediate filaments and a specific marker for astrocytes. Alterations in levels of GFAP may reflect pathological regulation of neuronal function and survival as well as abnormal synaptogenesis and neurotransmission. We employed quantitative gel electrophoresis and Western blotting to measure levels of GFAP in cerebella of 60 subjects divided equally among schizophrenia, bipolar disorder, major depression, and normal controls. GFAP levels were reduced by 32%, 17% and 14.5% in depressed, bipolar, and schizophrenic cerebella, respectively, versus controls. Only the depressed value was significantly different (p=0.015 Post-hoc Bonferroni test). Measurement of beta-actin levels showed no differences between the various groups. No significant effects of confounding variables were found. This is the first demonstration of GFAP reductions in cerebellum of subjects with mood disorders and schizophrenia, thereby adding to the reports of reductions in GFAP/glial cell counts in other brain regions of subjects with major depression, thus suggesting a downregulation of glial function in this disorder.     

Glial expression of fibroblast growth factor-9 in rat central nervous system.

We examined the expression of fibroblast growth factor (FGF)-9 in the rat central nervous system (CNS) by immunohistochemistry and in situ hybridization studies. FGF-9 immunoreactivity was conspicuous in motor neurons of the spinal cord, Purkinje cells, and neurons in the hippocampus and cerebral cortex. In addition to the neuronal localization of FGF-9 immunoreactivity that we reported previously, the present double-label immunohistochemistry clearly demonstrated that the immunoreactivity was present in glial fibrillary acidic protein (GFAP)-positive astrocytes preferentially present in the white matter of spinal cord and brainstem of adult rats and in CNPase-positive oligodendrocytes that were arranged between the fasciculi of nerve fibers in cerebellar white matter and corpus callosum of both adult and young rats. There was a tendency for FGF-9 immunoreactivity in oligodendrocytes to be more pronounced in young rats than in adult rats. The variation of oligodendrocyte FGF-9 immunoreactivity in adult rats was also more pronounced than that in young rats. With in situ hybridization, FGF-9 mRNA was observed in astrocytes in the white matter of rat spinal cord and oligodendrocytes in the white matter of cerebellum and corpus callosum of adult and young rats. The expression of FGF-9 mRNA in glial cells was lower than in neurons, and not all glial cells expressed FGF-9. In the present study, we demonstrated that FGF-9 was expressed not only in neurons but also in glial cells in the CNS. FGF-9 was considered to have important functions in adult and developing CNS.     

Expression of cellular prion protein (PrP<Superscript>c</Superscript>) in schizophrenia,bipolar disorder,and depression

Cellular prion protein (PrP(c)) is a copper-binding, membrane-attached GPI-anchored glycoprotein characterized by a high degree of amino acid sequence conservation among mammals. PrP(c) expression has been demonstrated in neurons, microglia, lymphocytes, and keratinocytes. Recently, the concept that PrP(c) may be involved in the defense against oxidative stress was advanced. In the present study, we used immunohistochemistry for PrP(c) to investigate 60 brains from the Stanley Neuropathology Consortium (15 controls, 15 patients with schizophrenia, 15 with bipolar disorder, and 15 with major depression). Rating scores as well as the numerical density of PrP(c)-positive and -negative neurons and glial cells were determined in the cingulate gyrus. All four groups showed a very high interindividual variation. PrP(c)-positive glial cells were significantly reduced in the white matter of patients with schizophrenia, bipolar disorder, and major depression. A similar result was obtained for the white matter in bipolar patients using rating scales. From the confounding variables, use of medication (i.e. antipsychotics, antidepressants, and mood stabilizers) had a significant effect on the expression of PrP(c) by neurons and glial cells. PrP(c)-immunoreactivities were significantly reduced for white matter glial cells in all examined groups. However, the results are not indicative for the occurrence of oxidative stress in the brains of schizophrenic and bipolar patients. Since the effect of antipsychotic and antidepressant medication as well as of mood stabilizers on the expression of PrP(c) was significant, it needs further clarification in experimental models.     

Glial fibrillary acidic protein in late life major depressive disorder: an immunocytochemical study

OBJECTIVES: Depression is a common psychiatric disorder in late life. Cerebrovascular disease has been postulated as an important aetiological factor in many cases (the "vascular depression" hypothesis). Consistent with this, an inflammatory response, most probably representing ischaemia, has been reported with increases in intercellular adhesion molecule 1 (ICAM-1), in the dorsolateral prefrontal cortex (DLPFC) in postmortem tissue from elderly depressed subjects. As ischaemia is known to cause astrogliosis, this study has further tested the "vascular depression hypothesis" by investigating the distribution of the astrocytic marker glial fibrillary acidic protein (GFAP) in the DLPFC and in the anterior cingulate cortex (ACC). METHODS: Postmortem tissue was obtained from 20 elderly patients with a history of major depressive disorder (MDD) and 20 control subjects. Sections were stained for GFAP using standard immunocytochemistry. Sets of images were obtained from all cortical layers in the DLPFC and ACC with the exception of layer IV in the ACC, and from gyral and deep white matter in both regions. The percentage of the area of each image occupied by GFAP was calculated using true colour image analysis, and mean values obtained for each region examined. RESULTS: Immunoreactivity for GFAP was low in grey matter (for example, Mean (SEM) 0.76 (0.2)% in DLPFC layer V in depressed subjects), but higher in white matter (for example, 12.02 (2.2)% in DLPFC deep white matter in depressed subjects). Pronounced gliosis was observed within grey matter in a few cases only. GFAP immunoreactivity was significantly higher in layer I of the DLPFC in depressed subjects 15.8 (2.6)% than in controls 9.7 (1.3)% (t=2.2; df=27.5, p=0.04). No difference was detected in any other region. CONCLUSIONS: The data suggest any increase in GFAP in elderly MDD patients is limited to layer 1 of the DLPFC. These results provide some support for the vascular depression hypothesis and further implicate DLPFC abnormalities in depression.