Prefrontal Cortex In Schizophrenia Research Articles

WHAT PROTEOMICS WILL ADD TO OUR UNDERSTANDING OF THE NEUROPATHOLOGY OF SCHIZOPHRENIA

Recent data suggest abnormalities of glutamate transmission in schizophrenia. While many findings of abnormal glutamate receptor expression in schizophrenia have been published, findings are subtle or even contradictory. These conflicting studies on the expression of these receptors leads to a reconsideration of the “glutamate hypothesis of schizophrenia” as not “too many” or “too few” receptors, but rather one of alterations in the cell biological processes that manage the total pool of receptors. Recent data point to abnormalities of glutamate receptor trafficking, delivery, dendritic localization, recycling, and degradation in the brain in schizophrenia. In this study, we extend our findings of abnormalities of intracellular trafficking of the AMPA subtype of glutamate receptor in schizophrenia. AMPA receptor trafficking starts in the endoplasmic reticulum (ER), in which AMPA receptor subunits are postranslationaly N-glycosylated. N-linked high mannose containing sugars added to AMPA subunits, which are trimmed and replaced by more elaborate sugars in the Golgi, after which AMPA subunits are trafficked for insertion into the plasma membrane. We assayed N-glycosylation status of AMPA subunits in prefrontal cortex in schizophrenia. N-glycosylation was assessed following digestion with endoglycosidase H (Endo H), which removes immature high mannose containing sugars, or with peptide-Nglycosidase F (PNGase F), which removes all N-linked sugars. We found that both GluR2 and GluR4 were sensitive to Endo H and PNGase F treatment, indicating that they are N-glycosylated; neither GluR1 nor GluR3 are N-glycosylated in human brain. GluR2 was found to have less N-linked high mannose and/or hybrid sugars in schizophrenia. This was confirmed by immunoprecipitation of GluR2 and probing with Concavalin A, a mannose-specific lectin. GluR2 immunoprecipitated from schizophrenia cortex was significantly less reactive to Con A comparing to the comparison group. These results indicate that GluR2 is abnormally glycosylated in schizophrenia, consistent with abnormal assembly or trafficking of the AMPA receptor. Abnormalities of glycosylation in schizophrenia may be more extensive, as we also have preliminary results suggesting abnormalities of Nglycosylation of NMDA subunits and two of the glutamate transporters. These results suggest that there are changes in glutamate receptors in schizophrenia that involve abnormalities of intracellular processes that effectively reduce receptor function even though total cellular levels of these receptors may be normal. Such findings are important because they point to the complexity of molecular and intracellular abnormalities in schizophrenia, and highlight novel sites that may be profitably targeted for drug.

ABNORMAL N-GLYCOSYLATION OF PROTEINS OF THE GLUTAMATE SYNAPSE IN SCHIZOPHRENIA

Recent data suggest abnormalities of glutamate transmission in schizophrenia. While many findings of abnormal glutamate receptor expression in schizophrenia have been published, findings are subtle or even contradictory. These conflicting studies on the expression of these receptors leads to a reconsideration of the “glutamate hypothesis of schizophrenia” as not “too many” or “too few” receptors, but rather one of alterations in the cell biological processes that manage the total pool of receptors. Recent data point to abnormalities of glutamate receptor trafficking, delivery, dendritic localization, recycling, and degradation in the brain in schizophrenia. In this study, we extend our findings of abnormalities of intracellular trafficking of the AMPA subtype of glutamate receptor in schizophrenia. AMPA receptor trafficking starts in the endoplasmic reticulum (ER), in which AMPA receptor subunits are postranslationaly N-glycosylated. N-linked high mannose containing sugars added to AMPA subunits, which are trimmed and replaced by more elaborate sugars in the Golgi, after which AMPA subunits are trafficked for insertion into the plasma membrane. We assayed N-glycosylation status of AMPA subunits in prefrontal cortex in schizophrenia. N-glycosylation was assessed following digestion with endoglycosidase H (Endo H), which removes immature high mannose containing sugars, or with peptide-Nglycosidase F (PNGase F), which removes all N-linked sugars. We found that both GluR2 and GluR4 were sensitive to Endo H and PNGase F treatment, indicating that they are N-glycosylated; neither GluR1 nor GluR3 are N-glycosylated in human brain. GluR2 was found to have less N-linked high mannose and/or hybrid sugars in schizophrenia. This was confirmed by immunoprecipitation of GluR2 and probing with Concavalin A, a mannose-specific lectin. GluR2 immunoprecipitated from schizophrenia cortex was significantly less reactive to Con A comparing to the comparison group. These results indicate that GluR2 is abnormally glycosylated in schizophrenia, consistent with abnormal assembly or trafficking of the AMPA receptor. Abnormalities of glycosylation in schizophrenia may be more extensive, as we also have preliminary results suggesting abnormalities of Nglycosylation of NMDA subunits and two of the glutamate transporters. These results suggest that there are changes in glutamate receptors in schizophrenia that involve abnormalities of intracellular processes that effectively reduce receptor function even though total cellular levels of these receptors may be normal. Such findings are important because they point to the complexity of molecular and intracellular abnormalities in schizophrenia, and highlight novel sites that may be profitably targeted for drug.

Increased Synaptic Dopamine Function in Associative Regions of the Striatum in Schizophrenia

A long-standing version of the dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic transmission at D(2) receptors in the limbic striatum is associated with the illness and that blockade of mesolimbic D(2) receptors is responsible for the antipsychotic action of D(2) receptor antagonists. To localize dopaminergic hyperactivity within the striatum in schizophrenia. Case-control study. Inpatient research unit. Eighteen untreated patients with schizophrenia and 18 healthy control subjects matched for age, sex, ethnicity, parental socioeconomic status, cigarette smoking, and weight. Percentage change in dopamine D(2) receptor availability in striatal subregions within each subject measured by positron emission tomography with carbon 11-labeled raclopride before and during pharmacologically induced dopamine depletion. In the associative striatum, acute dopamine depletion resulted in a larger increase in D(2) receptor availability in patients with schizophrenia (mean [SD], 15% [7%]) than in control subjects (10% [7%], P = .045), suggesting higher synaptic dopamine concentration. Within the associative striatum, this effect was most pronounced in the precommissural dorsal caudate (15% [8%] in patients vs 9% [8%] in controls, P = .03). No between-group differences were observed in the limbic and sensorimotor striatum. These findings suggest that schizophrenia is associated with elevated dopamine function in associative regions of the striatum. Because the precommissural dorsal caudate processes information from the dorsolateral prefrontal cortex, this observation also suggests that elevated subcortical dopamine function might adversely affect performance of the dorsolateral prefrontal cortex in schizophrenia. On the other hand, the absence of a group difference in the limbic striatum brings into question the therapeutic relevance of the mesolimbic selectivity of second-generation antipsychotic drugs.

Expression of the NR2B‐NMDA receptor subunit and its Tbr‐1/CINAP regulatory proteins in postmortem brain suggest altered receptor processing in schizophrenia

Several lines of evidence implicate aberrant glutamate neurotransmission in the pathophysiology of schizophrenia. In particular, compromised signaling through the N-methyl-D-aspartate (NMDA) receptor has been linked to positive, negative, and cognitive symptoms of this illness. Studies in postmortem brain have identified altered expression of several structural and signaling molecules of the postsynaptic density (PSD), including the abundantly expressed protein PSD-95, which binds directly to NR2 subunits of the NMDA receptor and regulates its trafficking, membrane expression, and downstream signaling. Several mechanisms for functional regulation of the NR2B-containing NMDA receptor, which have been linked to cognitive dysfunction in schizophrenia, are well known. To analyze whether early events in NR2B processing are affected in schizophrenia, we have isolated a subcellular endoplasmic reticulum (ER)-enriched fraction from postmortem brain and analyzed expression of the NR1 and NR2B NMDA receptor subunits as well as PSD-95 in two areas of prefrontal cortex. We found significantly decreased ER expression of NR2B and PSD-95 in dorsolateral prefrontal cortex in schizophrenia. Analysis in total-cell homogenates from the same subjects of NR2B and PSD-95 expression, as well as of the CINAP and Tbr-1 transcription regulatory proteins, indicate that changes in NR2B processing in schizophrenia involve increased ER exit of NR2B containing NMDA receptors.

A comparative study of MAP2 immunostaining in areas 9 and 17 in schizophrenia and Huntington chorea

Increasing evidence suggests that there may be significant morphological changes in the neuropil of the dorsolateral prefrontal cortex in schizophrenia. A controversial issue surrounding these deficits in the cortical neuropil is the confounding effects of antipsychotic (neuroleptic) medication as well as the question of generality to psychiatric disorders. To begin to address these issues we examined brains from Huntington’s patients matched to a cohort of schizophrenics and controls. Many Huntington’s patients take neuroleptics similar to schizophrenics; therefore, by comparing the two groups to controls we can begin to determine if neuroleptics play a role in the deficits reported in schizophrenia. Using MAP2 immunohistochemistry and thionin staining eight matched triplets of Huntington, schizophrenia and control, in areas 9 and 17 layers III and V were analyzed. Our results confirmed previous published data showing a schizophrenia-associated decrease in MAP2 in area 9 with no change in area 17. Similarly the Huntington’s patients showed no change in area 9 layer III and no change in area 17. There was however, a modest decrease observed in layer V area 9 of the Huntington’s patients. Neuron density measurements showed no change in either layer or brain region in any of the diagnostic categories. These observations suggest that antipsychotic medication may not be responsible for some of the morphological changes observed in the neuropil of the PFC in schizophrenia.

Infragranular gene expression disturbances in the prefrontal cortex in schizophrenia: Signature of altered neural development?

The development of the human neocortex gives rise to a complex cytoarchitecture, grouping together cells with similar structure, connectivity and function. As a result, the six neocortical laminae show distinct molecular content. In schizophrenia, many anatomical and neurochemical changes appear to be restricted to a subset of lamina and/or cell types. In this study, we hypothesized that supragranular (SG; laminae II–III) and infragranular layers (IG; laminae V–VI) of area 46 in the human prefrontal cortex will show distinct and specific transcriptome alterations between subjects with schizophrenia and matched controls. To enhance sample homogeneity, we compared the gene expression patterns of the SG and IG layers of 8 matched middle-aged male subjects with schizophrenia to 8 pairwise matched controls using two replicate DNA microarrays for each sample. The study revealed strong disease-related laminar expression differences between the SG and IG layers. Expression changes were dominated by an overall underexpression of the IG-enriched genes in the schizophrenia subjects compared to normal control subjects. Furthermore, using a diagnosis-blind, unsupervised clustering of the control-derived SG or IG-enriched transcripts, the IG-enriched markers segregated the subjects with schizophrenia from the matched controls with a high degree of confidence. Importantly, multiple members of the semaphorin gene family reported altered gene expression, suggesting that the IG gene expression disturbances in subjects with schizophrenia may be a result of altered cortical development and disrupted brain connectivity.

Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia

BackgroundWe have previously reported that the expression of the messenger ribonucleic acid (mRNA) for the NR2A subunit of the N-methyl-D-aspartate (NMDA) class of glutamate receptor was decreased in a subset of inhibitory interneurons in the cerebral cortex in schizophrenia. In this study, we sought to determine whether a deficit in the expression of NR2A mRNA was present in the subset of interneurons that contain the calcium buffer parvalbumin (PV) and whether this deficit was associated with a reduction in glutamatergic inputs in the prefrontal cortex (PFC) in schizophrenia.MethodsWe examined the expression of NR2A mRNA, labeled with a 35S-tagged riboprobe, in neurons that expressed PV mRNA, visualized with a digoxigenin-labeled riboprobe via an immunoperoxidase reaction, in twenty schizophrenia and twenty matched normal control subjects. We also immunohistochemically labeled the glutamatergic axon terminals with an antibody against vGluT1.ResultsThe density of the PV neurons that expressed NR2A mRNA was significantly decreased by 48-50% in layers 3 and 4 in the subjects with schizophrenia, but the cellular expression of NR2A mRNA in the PV neurons that exhibited a detectable level of this transcript was unchanged. In addition, the density of vGluT1-immunoreactive boutons was significantly decreased by 79% in layer 3, but was unchanged in layer 5 of the PFC in schizophrenia.ConclusionThese findings suggest that glutamatergic neurotransmission via NR2A-containing NMDA receptors on PV neurons in the PFC may be deficient in schizophrenia. This may disinhibit the postsynaptic excitatory circuits, contributing to neuronal injury, aberrant information flow and PFC functional deficits in schizophrenia.

Anterior hippocampal and orbitofrontal cortical structural brain abnormalities in association with cognitive deficits in schizophrenia

Objective Numerous studies have implicated the hippocampus and prefrontal cortex in schizophrenia. However, precisely which subregions of the hippocampus and prefrontal cortex are abnormal remain unknown. Our study goal was to investigate the structure of the anterior hippocampus, posterior hippocampus, dorsolateral prefrontal cortex (DLPFC), and orbitofrontal cortex (OFC) simultaneously in thirty-eight patients with schizophrenia and twenty-nine controls to determine which of these subregions are abnormal in schizophrenia. As an exploratory study goal, we investigated the relation of neurocognition to brain structure in schizophrenia patients. Method We generated detailed structural magnetic resonance imaging data and compared hippocampal and prefrontal subregional structural brain volumes between schizophrenia and control groups. We obtained a neurocognitive test battery in schizophrenia patients and studied the association of abnormal brain structures to neurocognition. Results Structural brain abnormalities were pinpointed to the left anterior hippocampus and left OFC in schizophrenia patients, which were both significantly reduced in volume. The DLPFC and posterior hippocampus, though numerically decreased in volume, were not significantly decreased. Anterior hippocampal volumes were more strongly associated with OFC volumes in schizophrenia patients compared to controls. By contrast, DLPFC volume was unrelated to anterior or posterior hippocampal volume. Both the anterior hippocampus and OFC were independently related to cognitive abnormalities common in schizophrenia, including indices of verbal, language, and executive functions. The DLPFC and posterior hippocampal volumes were unrelated to cognitive measures. Conclusions These findings highlight related abnormalities of the anterior hippocampus and OFC in schizophrenia, which may shed light on the pathophysiology of the disorder.

Nonlinear Response of the Anterior Cingulate and Prefrontal Cortex in Schizophrenia as a Function of Variable Attentional Control

Previous studies have reported abnormal prefrontal and cingulate activity during attentional control processing in schizophrenia. However, it is not clear how variation in attentional control load modulates activity within these brain regions in this brain disorder. The aim of this study in schizophrenia is to investigate the impact of increasing levels of attentional control processing on prefrontal and cingulate activity. Blood oxygen level-dependent (BOLD) responses of 16 outpatients with schizophrenia were compared with those of 21 healthy subjects while performing a task eliciting increasing levels of attentional control during event-related functional magnetic resonance imaging at 3 T. Results showed reduced behavioral performance in patients at greater attentional control levels. Imaging data indicated greater prefrontal activity at intermediate attentional control levels in patients but greater prefrontal and cingulate responses at high attentional control demands in controls. The BOLD activity profile of these regions in controls increased linearly with increasing cognitive loads, whereas in patients, it was nonlinear. Correlation analysis consistently showed differential region and load-specific relationships between brain activity and behavior in the 2 groups. These results indicate that varying attentional control load is associated in schizophrenia with load- and region-specific modification of the relationship between behavior and brain activity, possibly suggesting earlier saturation of cognitive capacity.

What Interferes with Inhibitory Functions in the Prefrontal Cortex in Schizophrenia

Cognitive impairments in schizophrenia have been linked to altered synthesis of γ-aminobutyric acid (GABA) receptors in the prefrontal cortex (PFC).

Proteome analysis of schizophrenia patients Wernicke's area reveals an energy metabolism dysregulation

BackgroundSchizophrenia is likely to be a consequence of DNA alterations that, together with environmental factors, will lead to protein expression differences and the ultimate establishment of the illness. The superior temporal gyrus is implicated in schizophrenia and executes functions such as the processing of speech, language skills and sound processing.MethodsWe performed an individual comparative proteome analysis using two-dimensional gel electrophoresis of 9 schizophrenia and 6 healthy control patients' left posterior superior temporal gyrus (Wernicke's area – BA22p) identifying by mass spectrometry several protein expression alterations that could be related to the disease.ResultsOur analysis revealed 11 downregulated and 14 upregulated proteins, most of them related to energy metabolism. Whereas many of the identified proteins have been previously implicated in schizophrenia, such as fructose-bisphosphate aldolase C, creatine kinase and neuron-specific enolase, new putative disease markers were also identified such as dihydrolipoyl dehydrogenase, tropomyosin 3, breast cancer metastasis-suppressor 1, heterogeneous nuclear ribonucleoproteins C1/C2 and phosphate carrier protein, mitochondrial precursor. Besides, the differential expression of peroxiredoxin 6 (PRDX6) and glial fibrillary acidic protein (GFAP) were confirmed by western blot in schizophrenia prefrontal cortex.ConclusionOur data supports a dysregulation of energy metabolism in schizophrenia as well as suggests new markers that may contribute to a better understanding of this complex disease.

Reduced neuronal expression of insulin-degrading enzyme in the dorsolateral prefrontal cortex of patients with haloperidol-treated, chronic schizophrenia

Insulin-degrading enzyme (IDE) is a neutral thiol metalloprotease, which cleaves insulin with high specificity. Additionally, IDE hydrolyzes Aβ, glucagon, IGF I and II, and β-endorphin. We studied the expression of IDE protein in postmortem brains of patients with schizophrenia and controls because: (1) the gene encoding IDE is located on chromosome 10q23–q25, a gene locus linked to schizophrenia; (2) insulin resistance with brain insulin receptor deficits/receptor dysfunction was reported in schizophrenia; (3) the enzyme cleaves IGF-I and IGF-II which are implicated in the pathophysiology of the disease; and (4) brain γ-endorphin levels, liberated from β-endorphin exclusively by IDE, have been reported to be altered in schizophrenia. We counted the number of IDE immunoreactive neurons in the dorsolateral prefrontal cortex, the hypothalamic paraventricular and supraoptic nuclei, and the basal nucleus of Meynert of 14 patients with schizophrenia and 14 matched control cases. Patients had long-term haloperidol treatment. In addition, relative concentrations of IDE protein in the dorsolateral prefrontal cortex were estimated by Western blot analysis. There was a significantly reduced number of IDE expressing neurons and IDE protein content in the left and right dorsolateral prefrontal cortex in schizophrenia compared with controls, but not in other brain areas investigated. Results of our studies on the influence of haloperidol on IDE mRNA expression in SHSY5Y neuroblastoma cells, as well as the effect of long-term treatment with haloperidol on the number of IDE immunoreactive neurons in rat brain, indicate that haloperidol per se, is not responsible for the decreased neuronal expression of the enzyme in schizophrenics. Haloperidol however, might exert some effect on IDE, through changes of the expression levels of its substrates IGF-I and II, insulin and β-endorphin. Reduced cortical IDE expression might be part of the disturbed insulin signaling cascades found in schizophrenia. Furthermore, it might contribute to the altered metabolism of certain neuropeptides (IGF-I and IGF-II, β-endorphin), in schizophrenia.

The quantitative neuropathology of schizophrenia

Schizophrenia is a devastating neuropsychiatric disorder showing a variety of cognitive disturbances in attention, working memory, verbal production, response monitoring and inhibition, in short, almost all aspects of information processing and evaluation. Equally diverse are the putative mechanisms that translate such deWcits into the anatomical substrates of schizophrenia pathology. Alterations in brain wiring and connectivity have long been suspected to play a key role in the development of schizophrenia. The resulting disorganization of neuronal systems in speciWc regions of the cerebral cortex and in certain subcortical structures may represent an anatomic and functional substrate for the constellation of symptoms that are typically observed in schizophrenic patients. To date, many studies have reported consistent and at times severe changes in the gray matter in schizophrenia and have paid attention to the connectivity of speciWc subsystems and particular populations of neurons. Reported abnormalities concern not only the numbers or densities of neurons but also their local microcircuitry and their distribution. Thus, altered densities and distribution of various populations of neurons have been reported in the prefrontal cortex in schizophrenia. Subclasses of interneurons are known to display abnormal localization in the subcortical white matter of the prefrontal cortex suggestive of cortical developmental pathology. Other data point to alterations of calretinin-containing interneurons, abnormal axonal terminals from inhibitory neurons, reduced gene expression of markers of inhibitory neurons, and to pathology of chandelier neuron axons endings on pyramidal cells in the prefrontal cortex of schizophrenic patients. Neuronal packing densities have been shown to be elevated in the prefrontal cortex of schizophrenic cases with a severe reduction in size of large layer III pyramidal cells, indicating that profound cellular attrition occurs during the progression of the disease. It has been proposed that such pathology of large projection neurons could be the result of altered inhibitory activity and an expression of excitotoxic damage. Comparable changes have been reported in the entorhinal cortex with abnormalities in neuronal distribution within the layer II clusters, as well as dendritic alterations, cell size reduction, and in certain subdomains of the entorhinal cortex, lower neuronal densities. A deWcit in synaptic transmission has also been suggested in schizophrenia based on reduced synaptophysin immunoreactivity in the prefrontal cortex as well as a severe impoverishment of the dendritic structure of pyramidal neurons and loss of dendritic spines. Finally, the thalamus has been the object of many studies of neuronal numbers showing that schizophrenia is accompanied by a variable loss of neurons at the nucleus or subnucleus level, suggesting a certain degree of regional speciWcity in the pathology that may diVerentially aVect speciWc sets of connections to the prefrontal cortex. It is worth noting that these alterations are speciWc to certain neural systems, as many regions of the brain do not show such changes. The concept of disrupted connectivity and abnormal synaptic transmission is key to our understanding of the cognitive and psychotic symptoms in schizophrenia. The involvement of the thalamoprefrontal pathway, together with the morphological alterations of prefrontal pyramidal P. R. Hof (&) · C. Schmitz Department of Neuroscience, Mount Sinai School of Medicine, Box 1065, One Gustave L. Levy Place, New York, NY 10029, USA e-mail: patrick.hof@mssm.edu

Fiber tracking of white matter integrity connecting the mediodorsal nucleus of the thalamus and the prefrontal cortex in schizophrenia: A diffusion tensor imaging study

The goal of this study was to detect abnormalities in white matter integrity connecting the mediodorsal nucleus of the thalamus and the prefrontal cortex using fiber-tracking technique. Diffusion tensor imaging was acquired in 20 patients with schizophrenia and 20 normal comparison subjects. Fiber tracking was performed on the anterior thalamic peduncle, and the tractography was used to determine the cross-sectional area, mean fractional anisotropy, and standard deviation of fractional anisotropy for every step separately in the right and left hemispheres. Compared with normal subjects, patients showed a significant reduction in the cross-sectional area of the left anterior thalamic peduncle. There were no significant differences for the mean fractional anisotropy bilaterally between the two groups, but significant differences for the standard deviation of fractional anisotropy in both hemispheres. Reduction in the cross-sectional area of the left anterior thalamic peduncle suggests the presence of the failure of left-hemisphere lateralization. In schizophrenic patients a significant increase of the standard deviation of fractional anisotropy raise the possibility that the inhomogeneity of white matter integrity, which is densely or sparsely distributed by site. These findings might provide further evidence for disruption of white matter integrity between the thalamus and the prefrontal cortex in schizophrenia.

Gray matter deficits in bipolar disorder are associated with genetic variability at interleukin‐1 beta gene (2q13)

Twin, family and recent molecular studies support the hypothesis of genetic overlapping between schizophrenia and bipolar disorder. Brain structural features shared by both psychiatric disorders might be the phenotypic expression of a common genetic risk background. Interleukin-1 (IL-1) cluster (chromosome 2q13) genetic variability, previously associated with an increased risk both for schizophrenia and for bipolar disorder, has been also associated with gray matter (GM) deficits, ventricular enlargement and hypoactivity of prefrontal cortex in schizophrenia. The aim of the present study was to analyze the influence of IL-1 cluster on brain morphology in bipolar disorder. Genetic variability at IL-1B and IL-1RN genes was analyzed in 20 DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition) bipolar patients. Magnetic resonance imaging (MRI) measurements were obtained for whole-brain GM and white matter, dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus, hippocampus and lateral ventricles. MRI data were corrected for age and cranial size using regression parameters from a group of 45 healthy subjects. A -511C/T polymorphism (rs16944) of IL-1B gene was associated with whole-brain GM deficits (P = 0.031) and left DLPFCGM deficits (P = 0.047) in bipolar disorder patients. These findings support the hypothesis of IL-1 cluster variability as a shared genetic risk factor contributing to GM deficits both in bipolar disorder and in schizophrenia. Independent replication in larger samples would be of interest to confirm these results.

Stereologic investigation of the posterior part of the hippocampus in schizophrenia

Structural magnetic resonance imaging and postmortem studies showed volume loss in the hippocampus in schizophrenia. The noted tissue reduction in the posterior section suggests that some cellular subfractions within this structure might be reduced in schizophrenia. To address this, we investigated numbers and densities of neurons, oligodendrocytes and astrocytes in the posterior hippocampal subregions in postmortem brains from ten patients with schizophrenia and ten matched controls using design-based stereology performed on Nissl-stained sections. Compared to the controls, the patients with schizophrenia showed a significant decrease in the mean number of oligodendrocytes in the left and right CA4. This is the first finding of reduced numbers of oligodendrocytes in CA4 of the posterior part of the hippocampus in schizophrenia. Our results are in line with earlier findings in the literature concerning decreased numbers of oligodendrocytes in the prefrontal cortex in schizophrenia. Our results may indicate disturbed connectivity of the CA4 of the posterior part of the hippocampus in schizophrenia and, thus, contribute to the growing number of studies showing the involvement of posterior hippocampal pathology in the pathophysiology of schizophrenia.

THE REVISED DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA: EVIDENCE FROM PHARMACOLOGICAL MRI STUDIES WITH ATYPICAL ANTIPSYCHOTIC MEDICATION

The revised dopamine (DA) hypothesis states that clinical symptoms of schizophrenia are caused by an imbalance of the DA system. In this article, we aim to review evidence for this hypothesis by evaluating functional magnetic resonance imaging studies in schizophrenia. Because atypical drugs are thought to have a normalizing effect on DA neurotransmission, we have focused on pharmacological MRI (PhMRI) studies that explore the effect of these drugs on prefrontal and striatal brain activity in schizophrenia patients. We encountered a total of 13 studies, most of which reported enhanced prefrontal activity associated with alleviation of negative symptoms and improvement of cognitive functions, following treatment with atypical antipsychotics. Besides increasing prefrontal cortex activity, atypical antipsychotics have also shown to be effective in the regulation of striatal functioning. The current PhMRI findings support the revised DA hypothesis of schizophrenia by confirming hypoactivity of the prefrontal cortex in schizophrenia and, following atypical antipsychotics, improvement of prefrontal and subcortical functions reflecting enhanced DA activity.

Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network?

Functional imaging studies using working memory tasks have documented both prefrontal cortex (PFC) hypo- and hyperactivation in schizophrenia. However, these studies have often failed to consider the potential role of task-related deactivation. Thirty-two patients with chronic schizophrenia and 32 age- and sex-matched normal controls underwent functional magnetic resonance imaging (fMRI) scanning while performing baseline, 1-back and 2-back versions of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups. The controls showed activation in the expected frontal regions. There were also clusters of deactivation, particularly in the anterior cingulate/ventromedial PFC and the posterior cingulate cortex/precuneus. Compared to the controls, the schizophrenic patients showed reduced activation in the right dorsolateral prefrontal cortex (DLPFC) and other frontal areas. There was also an area in the anterior cingulate/ventromedial PFC where the patients showed apparently greater activation than the controls. This represented a failure of deactivation in the schizophrenic patients. Failure to activate was a function of the patients' impaired performance on the n-back task, whereas the failure to deactivate was less performance dependent. Patients with schizophrenia show both failure to activate and failure to deactivate during performance of a working memory task. The area of failure of deactivation is in the anterior prefrontal/anterior cingulate cortex and corresponds to one of the two midline components of the 'default mode network' implicated in functions related to maintaining one's sense of self.

Disease-specific alterations in glutamatergic neurotransmission on inhibitory interneurons in the prefrontal cortex in schizophrenia

Glutamatergic modulation of inhibitory interneurons plays a crucial role in shaping the flow of information in the cerebral cortex. In a cohort of postmortem human brains from schizophrenia ( n = 20), bipolar disorder ( n = 20) and normal control ( n = 20) subjects, we colocalized the mRNA for the N-methyl- d-aspartate (NMDA) receptor NR2A subunit, labeled with [ 35S], and the mRNA for the γ-aminobutyric acid (GABA) synthesizing enzyme glutamic acid decarboxylase (GAD) 67, labeled with digoxigenin. We found that the density of GAD 67+ neurons in layers 2–5 of the prefrontal cortex was decreased by 27–36% in both schizophrenia and bipolar disorder. In addition, the density of the GAD 67+/NR2A+ neurons was decreased by 57% and 49% in layers 3 and 4, respectively, in schizophrenia, but it was unchanged in bipolar disorder. These findings raise the possibility that glutamatergic innervation of inhibitory interneurons via the NMDA receptor in the prefrontal cortex may be selectively altered in schizophrenia.

Volume reduction of dorsolateral prefrontal cortex in schizophrenia: A high resolution imaging study

Volume reduction of dorsolateral prefrontal cortex in schizophrenia: A high resolution imaging study