Prefrontal Cortex Of Schizophrenic Patients Research Articles

ERVW-1 Activates ATF6-Mediated Unfolded Protein Response by Decreasing GANAB in Recent-Onset Schizophrenia.

Schizophrenia, a mental disorder, afflicts 1% of the worldwide population. The dysregulation of homeostasis in the endoplasmic reticulum (ER) has been implicated in schizophrenia. Moreover, recent studies indicate that ER stress and the unfolded protein response (UPR) are linked to this mental disorder. Our previous research has verified that endogenous retrovirus group W member 1 envelope (ERVW-1), a risk factor for schizophrenia, is elevated in individuals with schizophrenia. Nevertheless, no literature is available regarding the underlying relationship between ER stress and ERVW-1 in schizophrenia. The aim of our research was to investigate the molecular mechanism connecting ER stress and ERVW-1 in schizophrenia. Here, we employed Gene Differential Expression Analysis to predict differentially expressed genes (DEGs) in the human prefrontal cortex of schizophrenic patients and identified aberrant expression of UPR-related genes. Subsequent research indicated that the UPR gene called XBP1 had a positive correlation with ATF6, BCL-2, and ERVW-1 in individuals with schizophrenia using Spearman correlation analysis. Furthermore, results from the enzyme-linked immunosorbent assay (ELISA) suggested increased serum protein levels of ATF6 and XBP1 in schizophrenic patients compared with healthy controls, exhibiting a strong correlation with ERVW-1 using median analysis and Mann-Whitney U analysis. However, serum GANAB levels were decreased in schizophrenic patients compared with controls and showed a significant negative correlation with ERVW-1, ATF6, and XBP1 in schizophrenic patients. Interestingly, in vitro experiments verified that ERVW-1 indeed increased ATF6 and XBP1 expression while decreasing GANAB expression. Additionally, the confocal microscope experiment suggested that ERVW-1 could impact the shape of the ER, leading to ER stress. GANAB was found to participate in ER stress regulated by ERVW-1. In conclusion, ERVW-1 induced ER stress by suppressing GANAB expression, thereby upregulating the expression of ATF6 and XBP1 and ultimately contributing to the development of schizophrenia.

Symposium Title: Causality Matters of Oscillation in Psychophysiologies

Both the molecular co-chaperone FKBP51 and the presynaptic vesicle protein synapsin (alternatively spliced from SYN1–3) are intensively discussed players in the still insufficiently explored pathobiology of psychiatric disorders such as major depression, schizophrenia and posttraumatic stress disorder (PTSD). To address their still unknown interaction, we compared the expression levels of synapsin and five other neurostructural and HPA axis related marker proteins in the prefrontal cortex (PFC) and the hippocampus of restrained-stressed and unstressed Fkbp5 knockout mice and corresponding wild-type littermates. In addition, we compared and correlated the gene expression levels of SYN1, SYN2 and FKBP5 in three different online datasets comprising expression data of human healthy subjects as well as of predominantly medicated patients with different psychiatric disorders. In summary, we found that Fkbp5 deletion, which we previously demonstrated to improve stress-coping behavior in mice, prevents the stress-induced decline in prefrontal cortical (pc), but not in hippocampal synapsin expression. Accordingly, pc, but not hippocampal, synapsin protein levels correlated positively with a more active mouse stress coping behavior. Searching for an underlying mechanism, we found evidence that deletion of Fkbp5 might prevent stress-induced pc synapsin loss, at least in part, through improvement of pc Akt kinase activity. These results, together with our finding that FKBP5 and SYN1 mRNA levels were regulated in opposite directions in the PFC of schizophrenic patients, who are known for exhibiting an altered stress-coping behavior, provide the first evidence of a role for pc synapsin in FKBP51 modulation of stress responsiveness. This role might extend to other tissues, as we found FKBP5 and SYN1 levels to correlate inversely not only in human PFC samples but also in other expression sites. The main limitation of this study is the small number of individuals included in the correlation analyses. Future studies will have to verify the here-postulated role of the FKBP51–Akt kinase–synapsin pathway in stress responsiveness.

Lack of Helios During Neural Development Induces Adult Schizophrenia-Like Behaviors Associated With Aberrant Levels of the TRIF-Recruiter Protein WDFY1.

The role of the WDFY1 protein has been studied as a TLR3/4 scaffold/recruiting protein in the immune system and in different oncogenic conditions. However, its function in brain remains poorly understood. We have found that in mice devoid of Helios (He–/– mice), a transcription factor specifically expressed during the development of the immune cells and the central nervous system, there is a permanent and sustained increase of Wdfy1 gene expression in the striatum and hippocampus. Interestingly, we observed that WDFY1 protein levels were also increased in the hippocampus and dorsolateral prefrontal cortex of schizophrenic patients, but not in the hippocampus of Alzheimer’s disease patients with an associated psychotic disorder. Accordingly, young He–/– mice displayed several schizophrenic-like behaviors related to dysfunctions in the striatum and hippocampus. These changes were associated with an increase in spine density in medium spiny neurons (MSNs) and with a decrease in the number and size of PSD-95-positive clusters in the stratum radiatum of the CA1. Moreover, these alterations in structural synaptic plasticity were associated with a strong reduction of neuronal NF-κB in the pyramidal layer of the CA1 in He–/– mice. Altogether, our data indicate that alterations involving the molecular axis Helios-WDFY1 in neurons during the development of core brain regions could be relevant for the pathophysiology of neuropsychiatric disorders such as schizophrenia.

The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia.

Dopamine is one of the neurotransmitters whose transmission is altered in a number of neural pathways in the brain of schizophrenic patients. Current evidence indicates that these alterations involve hyperactive dopaminergic transmission in mesolimbic areas, striatum, and hippocampus, whereas hypoactive dopaminergic transmission has been reported in the prefrontal cortex of schizophrenic patients. Consequently, schizophrenia is associated with several cognitive and behavioral alterations. Of note, the immune system has been found to collaborate with the central nervous system in a number of cognitive and behavioral functions, which are dysregulated in schizophrenia. Moreover, emerging evidence has associated schizophrenia and inflammation. Importantly, different lines of evidence have shown dopamine as a major regulator of inflammation. In this regard, dopamine might exert strong regulation in the activity, migration, differentiation, and proliferation of immune cells that have been shown to contribute to cognitive functions, including T-cells, microglial cells, and peripheral monocytes. Thereby, alterations in dopamine levels associated to schizophrenia might affect inflammatory response of immune cells and consequently some behavioral functions, including reference memory, learning, social behavior, and stress resilience. Altogether these findings support the involvement of an active cross-talk between the dopaminergic and immune systems in the physiopathology of schizophrenia. In this review we summarize, integrate, and discuss the current evidence indicating the involvement of an altered dopaminergic regulation of immunity in schizophrenia.

Alterations of perineuronal nets in the dorsolateral prefrontal cortex of neuropsychiatric patients

BackgroundAlterations in the structure and physiology of interneurons in the prefrontal cortex (PFC) are important factors in the etiopathology of different psychiatric disorders. Among the interneuronal subpopulations, parvalbumin (PV) expressing cells appear to be specially affected. Interestingly, during development and adulthood the connectivity of these interneurons is regulated by the presence of perineuronal nets (PNNs), specialized regions of the extracellular matrix, which are frequently surrounding PV expressing neurons. Previous reports have found anomalies in the density of PNNs in the PFC of schizophrenic patients. However, although some studies have described alterations in PNNs in some extracortical regions of bipolar disorder patients, there are no studies focusing on the prefrontocortical PNNs of bipolar or major depression patients. For this reason, we have analyzed the density of PNNs in post-mortem sections of the dorsolateral PFC (DLPFC) from the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients.ResultsWe have not observed differences in the distribution of PV+ cells or PNNs, or in the percentage of PV+ interneurons surrounded by PNNs. The density of PV+ interneurons was similar in all the experimental groups, but there was a significantly lower density of PNNs in the DLPFC of bipolar disorder patients and a tendency towards a decrease in schizophrenic patients. No differences were found when evaluating the density of PV+ cells surrounded by PNNs. Interestingly, when assessing the influence of demographic data, we found an inverse correlation between the density of PNNs and the presence of psychosis.ConclusionsThe present results point to prefrontocortical PNNs and their role in the regulation of neuronal plasticity as putative players in the etiopathology of bipolar disorder and schizophrenia. Our findings also suggest a link between these specialized regions of the extracellular matrix and the presence of psychosis.

Altered Expression Profile of IgLON Family of Neural Cell Adhesion Molecules in the Dorsolateral Prefrontal Cortex of Schizophrenic Patients.

Neural adhesion proteins are crucial in the development and maintenance of functional neural connectivity. Growing evidence suggests that the IgLON family of neural adhesion molecules LSAMP, NTM, NEGR1, and OPCML are important candidates in forming the susceptibility to schizophrenia (SCZ). IgLON proteins have been shown to be involved in neurite outgrowth, synaptic plasticity and neuronal connectivity, all of which have been shown to be altered in the brains of patients with the diagnosis of schizophrenia. Here we optimized custom 5′-isoform-specific TaqMan gene-expression analysis for the transcripts of human IgLON genes to study the expression of IgLONs in the dorsolateral prefrontal cortex (DLPFC) of schizophrenic patients (n = 36) and control subjects (n = 36). Uniform 5′-region and a single promoter was confirmed for the human NEGR1 gene by in silico analysis. IgLON5, a recently described family member, was also included in the study. We detected significantly elevated levels of the NEGR1 transcript (1.33-fold increase) and the NTM 1b isoform transcript (1.47-fold increase) in the DLPFC of schizophrenia patients compared to healthy controls. Consequent protein analysis performed in male subjects confirmed the increase in NEGR1 protein content both in patients with the paranoid subtype and in patients with other subtypes. In-group analysis of patients revealed that lower expression of certain IgLON transcripts, mostly LSAMP 1a and 1b, could be related with concurrent depressive endophenotype in schizophrenic patients. Additionally, our study cohort provides further evidence that cannabis use may be a relevant risk factor associated with suicidal behaviors in psychotic patients. In conclusion, we provide clinical evidence of increased expression levels of particular IgLON family members in the DLPFC of schizophrenic patients. We propose that alterations in the expression profile of IgLON neural adhesion molecules are associated with brain circuit disorganization in neuropsychiatric disorders, such as schizophrenia. In the light of previously published data, we suggest that increased level of NEGR1 in the frontal cortex may serve as molecular marker for a wider spectrum of psychiatric conditions.

Schizophrenia and reelin: a model based on prenatal stress to study epigenetics, brain development and behavior.

Schizophrenia is a severe psychiatric disorder that results in a significant disability for the patient. The disorder is characterized by impairment of the adaptive orchestration of actions, a cognitive function that is mainly dependent on the prefrontal cortex. This behavioral deficit, together with cellular and neurophysiological alterations in the prefrontal cortex, as well as reduced density of GABAergic cells and aberrant oscillatory activity, all indicate structural and functional deficits of the prefrontal cortex in schizophrenia. Among the several risk factors for the development of schizophrenia, stress during the prenatal period has been identified as crucial. Thus, it is proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairment observed in schizophrenia. However, the precise mechanisms that link prenatal stress with the impairment of prefrontal cortex function is largely unknown. Reelin is an extracellular matrix protein involved in the development of cortical neural connectivity at embryonic stages, and in synaptic plasticity at postnatal stages. Interestingly, down-regulation of reelin expression has been associated with epigenetic changes in the reelin gene of the prefrontal cortex of schizophrenic patients. We recently showed that, similar to schizophrenic patients, prenatal stress induces down-expression of reelin associated with the methylation of its promoter in the rodent prefrontal cortex. These alterations were paralleled with altered prefrontal cortex functional connectivity and impairment in prefrontal cortex-dependent behavioral tasks. Therefore, considering molecular, cellular, physiological and behavioral evidence, we propose a unifying framework that links prenatal stress and prefrontal malfunction through epigenetic alterations of the reelin gene.

Semaphorin and plexin gene expression is altered in the prefrontal cortex of schizophrenia patients with and without auditory hallucinations

Auditory hallucinations (AH) are clinical hallmarks of schizophrenia, however little is known about molecular genetics of these symptoms. In this study, gene expression profiling of postmortem brain samples from prefrontal cortex of schizophrenic patients without AH (SNA), patients with AH (SA) and control subjects were compared. Genome-wide expression analysis was conducted using samples of three individuals of each group and the Affymetrix GeneChip Human-Gene 1.0 ST-Array. This analysis identified the Axon Guidance pathway as one of the most differentially expressed network among SNA, SA and CNT. To confirm the transcriptome results, mRNA level quantification of seventeen genes involved in this pathway was performed in a larger sample. PLXNB1, SEMA3A, SEMA4D and SEM6C were upregulated in SNA or SA patients compared to controls. PLXNA1 and SEMA3D showed down-regulation in their expression in the patient’s samples, but differences remained statistically significant between the SNA patients and controls. Differences between SNA and SA were found in PLXNB1 expression which is decreased in SA patients. This study strengthens the contribution of brain plasticity in pathophysiology of schizophrenia and shows that non-hallucinatory patients present more alterations in frontal regions than patients with hallucinations concerning neural plasticity.

A Role for D-aspartate Oxidase in Schizophrenia and in Schizophrenia-related Symptoms Induced by Phencyclidine in Mice.

Introduction D-aspartate (D-Asp) is an atypical amino acid that binds to and activates NMDARs. D-Asp occurs abundantly in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-Aspartate Oxidase (DDO). The agonistic activity of D-Asp on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for NMDAR-related alterations observed in schizophrenia. Consistently, substantial reduction of D-Asp was observed in post-mortem schizophrenia brains. Aims We evaluated the potential contribution of D-Asp as neurodevelopmental modulator of brain circuits and behaviors relevant to schizophrenia. Objectives We analyzed DDO mRNA expression in the post-mortem prefrontal cortex of schizophrenic patients. Moreover, we treated knockout mice for Ddo gene ( Ddo -/- ) with the NMDAR antagonist phencyclidine to evaluate their schizophrenia-relevant behaviors and circuits. Finally, we assessed cortico-hippocampal connectivity of these mice. Methods DDO mRNA detection was performed by quantitative PCR. Phencyclidine-induced schizophrenia-like behaviours were assessed through motor activity and prepulse inhibition paradigms. Resting-state and pharmacological fMRI were used to evaluate functional circuits and connectivity. Results DDO mRNA expression is increased in frontal samples of schizophrenic patients. In mice, the absence of Ddo gene produces a significant reduction in phencyclidine-induced motor hyper-activity and prepulse inhibition deficit. Furthermore, increased levels of D-Asp in Ddo -/- animals significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in schizophrenia. Conclusions Our data suggest that D-Asp, through the regulation exerted by DDO, may have a role in the pathophysiology of schizophrenia.

A role for D-aspartate oxidase in schizophrenia and in schizophrenia-related symptoms induced by phencyclidine in mice.

Increasing evidence points to a role for dysfunctional glutamate N-methyl-D-aspartate receptor (NMDAR) neurotransmission in schizophrenia. D-aspartate is an atypical amino acid that activates NMDARs through binding to the glutamate site on GluN2 subunits. D-aspartate is present in high amounts in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-aspartate oxidase (DDO). The agonistic activity exerted by D-aspartate on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for some of the NMDAR-related alterations observed in schizophrenia. Consistently, substantial reductions of D-aspartate and NMDA were recently observed in the postmortem prefrontal cortex of schizophrenic patients. Here we show that DDO mRNA expression is increased in prefrontal samples of schizophrenic patients, thus suggesting a plausible molecular event responsible for the D-aspartate imbalance previously described. To investigate whether altered D-aspartate levels can modulate schizophrenia-relevant circuits and behaviors, we also measured the psychotomimetic effects produced by the NMDAR antagonist, phencyclidine, in Ddo knockout mice (Ddo−/−), an animal model characterized by tonically increased D-aspartate levels since perinatal life. We show that Ddo−/− mice display a significant reduction in motor hyperactivity and prepulse inhibition deficit induced by phencyclidine, compared with controls. Furthermore, we reveal that increased levels of D-aspartate in Ddo−/− animals can significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico–hippocampal connectivity networks potentially involved in schizophrenia. Collectively, the present results suggest that altered D-aspartate levels can influence neurodevelopmental brain processes relevant to schizophrenia.

A role for synapsin in FKBP51 modulation of stress responsiveness: Convergent evidence from animal and human studies

Both the molecular co-chaperone FKBP51 and the presynaptic vesicle protein synapsin (alternatively spliced from SYN1-3) are intensively discussed players in the still insufficiently explored pathobiology of psychiatric disorders such as major depression, schizophrenia and posttraumatic stress disorder (PTSD). To address their still unknown interaction, we compared the expression levels of synapsin and five other neurostructural and HPA axis related marker proteins in the prefrontal cortex (PFC) and the hippocampus of restrained-stressed and unstressed Fkbp5 knockout mice and corresponding wild-type littermates. In addition, we compared and correlated the gene expression levels of SYN1, SYN2 and FKBP5 in three different online datasets comprising expression data of human healthy subjects as well as of predominantly medicated patients with different psychiatric disorders. In summary, we found that Fkbp5 deletion, which we previously demonstrated to improve stress-coping behavior in mice, prevents the stress-induced decline in prefrontal cortical (pc), but not in hippocampal synapsin expression. Accordingly, pc, but not hippocampal, synapsin protein levels correlated positively with a more active mouse stress coping behavior. Searching for an underlying mechanism, we found evidence that deletion of Fkbp5 might prevent stress-induced pc synapsin loss, at least in part, through improvement of pc Akt kinase activity. These results, together with our finding that FKBP5 and SYN1 mRNA levels were regulated in opposite directions in the PFC of schizophrenic patients, who are known for exhibiting an altered stress-coping behavior, provide the first evidence of a role for pc synapsin in FKBP51 modulation of stress responsiveness. This role might extend to other tissues, as we found FKBP5 and SYN1 levels to correlate inversely not only in human PFC samples but also in other expression sites. The main limitation of this study is the small number of individuals included in the correlation analyses. Future studies will have to verify the here-postulated role of the FKBP51-Akt kinase-synapsin pathway in stress responsiveness.

Altered fatty acid concentrations in prefrontal cortex of schizophrenic patients

BackgroundDisturbances in prefrontal cortex phospholipid and fatty acid composition have been reported in patients with schizophrenia (SCZ), often as an incomplete lipid profile or a percent of total lipid concentration. In this study, we quantified absolute concentrations (nmol/g wet weight) and fractional concentrations (i.e. percent of total fatty acids) of several lipid classes and their constituent fatty acids in postmortem prefrontal cortex of SCZ patients (n = 10) and age-matched controls (n = 10). MethodsLipids were extracted, fractionated with thin layer chromatography and assayed. ResultsMean total lipid, phospholipid, individual phospholipids, plasmalogen, triglyceride and cholesteryl ester concentrations did not differ significantly between the groups. Compared to controls, SCZ brains showed significant increases in several monounsaturated and polyunsaturated fatty acid absolute concentrations in cholesteryl ester. Significant increases or decreases occurred in palmitoleic, linoleic, γ-linolenic and n-3 docosapentaenoic acid absolute concentrations in total lipids, triglycerides or phospholipids. Changes in fractional concentrations did not consistently reflect absolute concentration changes. ConclusionThese findings suggest disturbed prefrontal cortex fatty acid absolute concentrations, particularly within cholesteryl esters, as a pathological aspect of schizophrenia.

Increased Brain Membrane Fluidity in Schizophrenia

Recent findings showing significant correlations between phospholipase A2 (PLA2) activity and structural changes in schizophrenic brains contribute to the membrane hypothesis of schizophrenia, which was hampered because a clean functional link between elevated PLA2 activity and brain structure was missing (Neuroimage, 2010; 52: 1314-1327). We measured membrane fluidity parameters and found that brain membranes isolated from the prefrontal cortex of schizophrenic patients showed significantly increased flexibility of fatty acid chains. Our findings support a possible link between elevated PLA2 activity in cortical areas of schizophrenic patients and subsequent alterations of the biophysical parameters of neuronal membranes leading to structural changes in these areas.

P02-346 - Findings of Spectrum Funcional MRI (SF-MRI) in Schizophrenia

IntroductionN-acetil-aspartate (NAA) is located inside the soma and dendrites. Its believed to be an indirect indicator of the metabolic activity of these cells. Phosphomonoesters (PME) are involved in synthesis of neuronal membranes and phosphodiesters (PDE) in its degradation. Glutamine, an aminoacid produced by glial cells, is transported into the neurone for its transformation into glutamate and gamma aminobutyric acid.MethodsReview clinical trials performed on schizophrenic patients with SF-MRI, with 31P y 1H, to measure concentration of NAA, PME, PDE and glutamine.ObjectivesDetecting chemichal alterations that could be used as indicators in schizophrenia.ResultsNAA concentration in temporal and frontal cortex of schizophrenic patients, are significantly lower than in healthy controls. In other trials, differences in NAA concentration (measured in prefrontal cortex) have not been found, comparing patients during their first psychotic episode and healthy controls. Lowered concentrations of PME and increased ones of PDE in prefrontal cortex of schizophrenic patients have been found. Glutamine levels are increased in schizophrenic patients, being directely correlated with the duration of the process. These levels are reduced when antipsychotic drugs are used.ConclusionsThe decrease on NAA levels at schizophrenia onset and on healthy relatives remark its value as an endophenotypical indicator, but not as an illness indicator. Changes on PME and PDE concentrations cannot be used as illness indicators. The increase on glutamine synthesis could be due to glutamatergic hypofunction in schizophrenic patients, but there are other factors that may cause it, so it cannot be used as an indicator.

Reducing Prefrontal Gamma-Aminobutyric Acid Activity Induces Cognitive, Behavioral, and Dopaminergic Abnormalities That Resemble Schizophrenia

Perturbations in gamma-aminobutyric acid (GABA)-related markers have been reported in the prefrontal cortex of schizophrenic patients. However, a preclinical assessment of how suppression of prefrontal cortex GABA activity may reflect behavioral and cognitive pathologies observed in schizophrenia is forthcoming. We assessed the effects of pharmacologic blockade of prefrontal cortex GABA(A) receptors in rats on executive functions and other behaviors related to schizophrenia, as well as neural activity of midbrain dopamine neurons. Blockade of prefrontal cortex GABA(A) receptors with bicuculline (12.5-50 ng) did not affect working memory accuracy but did increase response latencies, resembling speed of processing deficits observed in schizophrenia. Prefrontal cortex GABA(A) blockade did not impede simple discrimination or reversal learning but did impair set-shifting in a manner dependent on when these treatments were given. Reducing GABA activity before the set-shift impaired the ability to acquire a novel strategy, whereas treatment before the initial discrimination increased perseveration during the shift. Latent inhibition was unaffected by bicuculline infusions before the preexposure/conditioning phases, suggesting that reduced prefrontal cortex GABA activity does not impair "learned irrelevance." GABA(A) blockade increased locomotor activity and showed synergic effects with a subthreshold dose of amphetamine. Furthermore, reducing medial prefrontal cortex GABA activity selectively increased phasic burst firing of ventral tegmental area dopamine neurons, without altering the their overall population activity. These results suggest that prefrontal cortex GABA hypofunction may be a key contributing factor to deficits in speed of processing, cognitive flexibility, and enhanced phasic dopamine activity observed 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

Learning potential on the WCST in schizophrenia is related to the neuronal integrity of the anterior cingulate cortex as measured by proton magnetic resonance spectroscopy

Background In recent years, schizophrenia has increasingly been recognized as a neurocognitive disorder, which has led to a growing literature on cognitive rehabilitation, and suggested several potential enhancements to cognitive function. For instance, it has been shown that executive functioning deficits as measured by the Wisconsin Card Sorting Test (WCST) can be modified in a subgroup of schizophrenic patients. The neurobiological basis of cognitive remediation has not been elucidated so far, although structural, functional and metabolic abnormalities of the prefrontal cortex have been associated with cognitive impairment. Methods In this study, learning potential was investigated in 43 schizophrenic patients and 37 age- and education-matched healthy controls, using a dynamic version of the WCST, which integrates instructions and feedback into the testing procedure. Performance was related to cerebral metabolism, assessed by single-voxel proton magnetic resonance spectroscopy of the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC). Results N-acetylaspartate (NAA), a marker of neuronal integrity, was significantly reduced in the DLPFC of schizophrenic patients as compared to the healthy control group. The level of NAA in the DLPFC positively correlated with performance in the dynamic WCST in healthy subjects, whereas in schizophrenic patients a significant correlation was observed between NAA and glutamate/glutamine in the ACC and learning potential. Conclusion These data imply a relationship between neuronal plasticity as assessed by learning potential and NAA levels of the prefrontal cortex in schizophrenic patients and healthy subjects, and suggest the involvement of differential neuronal networks in learning for schizophrenic patients compared to healthy controls.

Chandelier cartridges in the prefrontal cortex are reduced in isolation reared rats

Chandelier neurons are a subset of parvalbumin containing cortical interneurons characterised by their preferential targeting of the axon initial segments of pyramidal neurons. They have been the focus of recent interest after evidence that the arrays of boutons are reduced in the prefrontal cortex of schizophrenic patients, post mortem. Since one chandelier neuron may innervate the axon initial segments of several hundred pyramidal neurons, it is hypothesized that their special connectivity might facilitate synchronisation of cortical outputs and play a key role in working memory. Disruption in their function is therefore thought to play a potentially important role in cortically associated symptoms of schizophrenia. Using the isolation rearing animal model of schizophrenia, we examined immunolabelling for GABA-transporter 1, a marker of chandelier cartridges. We show that the numbers of arrays of chandelier axons are reduced by 36% in the ventral prelimbic cortex of isolation-reared rats, compared with their socially-housed litter mates. This mimics findings in the PFC of schizophrenic patients where GAT-1-positive cartridges are reduced by 40% and is the first study to demonstrate changes in chandelier cartridges in an animal model of schizophrenia.

Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients

Neuregulin-1 (NRG1) and its receptor, ErbB4, have been implicated in schizophrenia at both gene and transcript levels. The present investigation compared NRG1 and ErbB4 protein levels in prefrontal cortical (PFC) cytoplasmic and nuclear fractions among normal, schizophrenic, bipolar and major depressed subjects from the Stanley Consortium. We used immunoblotting procedures to examine potential NRG1 and ErbB4 immunoreactive bands, but specifically quantified NRG1 immunoreactive signals at 42, 48 and 53 kDa and ErbB4 immunoreactive signals at 21, 55, 60 and 180 kDa. PFC cytoplasmic 53 kDa NRG1 protein levels were significantly increased (~ 20%) in schizophrenic patients relative to each of the other subject groups. We also detected diagnostic effects on PFC cytoplasmic full-length (180 kDa) ErbB4 protein levels, and post hoc tests revealed that these quantities were significantly increased (~ 30%) in schizophrenic patients relative to normal and to depressed subjects. In addition, we examined the levels of potential ErbB4 cleavage products at 21, 55 and 60 kDa relative to those of full-length ErbB4 in the PFC fractions. We detected trends for diagnostic effects on PFC cytoplasmic 21 kDa/180 kDa and 55 kDa/180 kDa ratios, and post hoc tests revealed that these ratios were significantly reduced in schizophrenic patients relative to normal individuals. Our investigation suggests that schizophrenia-associated NRG1 and ErbB4 mRNA elevations also occur at the protein level and may be specific to schizophrenia. We hypothesize that ErbB4 proteolytic processing may also be altered in schizophrenia, yielding altered ratios of functionally distinct forms of ErbB4.

Immunohistochemical Evidence for Impaired Neuregulin‐1 Signaling in the Prefrontal Cortex in Schizophrenia and in Unipolar Depression

In the central nervous system (CNS), neuregulin-1 (NRG-1) proteins function in neuronal migration, differentiation, and survival of oligodendrocytes. The NRG-1 gene codes for at least 15 different isoforms, which may be classified on the basis of their molecular structure. At least two different haplotypes of the NRG-1 gene may be associated with schizophrenia. An abnormal expression pattern of NRG-1 mRNA was found in the prefrontal cortex of schizophrenic patients in comparison to controls. We here show that the NRG-1alpha isoform is significantly reduced in white matter of the prefrontal cortex in schizophrenia but not in affective disorder. In the prefrontal gray matter, the density of NRG-1alpha expressing neurons was reduced in individuals with schizophrenia and in unipolar patients. We studied brains of 22 schizophrenics, 12 patients with affective disorders (7 unipolar and 5 bipolar), and 22 matched controls. NRG-1alpha immunoreactive material was detected with a polyclonal antiserum against the synthetic peptide from alpha-type EGF-like domain of human NRG. The demonstrated decreased number of NRG-1 immunoreactive neurons in the brains of schizophrenics and patients with unipolar depression points to an important role of this NRG-1alpha splice variant in neuropsychiatric disorders. Reduced NRG-1alpha protein concentrations were found in brains of schizophrenics after Western blot analysis. The diminished expression of NRG-1alpha strongly supports an early neurodevelopmental component to schizophrenia.