Cells In Schizophrenia Research Articles

Causal role of immune cells in schizophrenia: Mendelian randomization (MR) study

BackgroundComplex immune-brain interactions that affect neural development, survival and function might have causal and therapeutic implications for psychiatric illnesses. However, previous studies examining the association between immune inflammation and schizophrenia (SCZ) have yielded inconsistent findings.MethodsComprehensive two-sample Mendelian randomization (MR) analysis was performed to determine the causal association between immune cell signatures and SCZ in this study. Based on publicly available genetic data, we explored causal associations between 731 immune cell signatures and SCZ risk. A total of four types of immune signatures (median fluorescence intensities (MFI), relative cell (RC), absolute cell (AC), and morphological parameters (MP)) were included. Comprehensive sensitivity analyses were used to verify the robustness, heterogeneity, and horizontal pleiotropy of the results.ResultsAfter FDR correction, SCZ had no statistically significant effect on immunophenotypes. It was worth mentioning some phenotypes with unadjusted low P-values, including FSC-A on NKT (β = 0.119, 95% CI = 0.044 ~ 0.194, P = 0.002), DN (CD4-CD8-) NKT %T cell (β = 0.131, 95% CI = 0.054 ~ 0.208, P = 9.03 × 10− 4), and SSC-A on lymphocytes (β = 0.136, 95% CI = 0.059 ~ 0.213, P = 5.43 × 10− 4). The causal effect of SCZ IgD on transitional was estimated to 0.127 (95% CI = 0.051 ~ 0.203, P = 1.09 × 10− 3). SCZ also had a causal effect on IgD+ %B cell (β = 0.130, 95% CI = 0.054 ~ 0.207, P = 8.69 × 10− 4), and DP (CD4+CD8+) %T cell (β = 0.131, 95% CI = 0.054 ~ 0.207, P = 8.05 × 10− 4). Furthermore, four immunophenotypes were identified to be significantly associated with SCZ risk: naive CD4+ %T cell (OR = 0.986, 95% CI = 0.979 ~ 0.992, P = 1.37 × 10− 5), HLA DR on CD14− CD16− (OR = 0.738 (95% CI = 0.642 ~ 0.849, P = 2.00 × 10− 5), CD33dim HLA DR+ CD11b− AC (OR = 0.631, 95% CI = 0.529 ~ 0.753, P = 3.40 × 10− 7) and activated & resting Treg % CD4 Treg (OR = 0.937, 95% CI = 0.906 ~ 0.970, P = 1.96 × 10− 4).ConclusionsOur study has demonstrated the close connection between immune cells and SCZ by genetic means, thus providing guidance for future clinical research.

Single-nucleus RNA sequencing of the midbrain blood-brain barrier cells in schizophrenia

Single-nucleus RNA sequencing of the midbrain blood-brain barrier cells in schizophrenia

Single-nucleus RNA sequencing of midbrain blood-brain barrier cells in schizophrenia reveals subtle transcriptional changes with overall preservation of cellular proportions and phenotypes

The midbrain is an extensively studied brain region in schizophrenia, in view of its reported dopamine pathophysiology and neuroimmune changes associated with this disease. Besides the dopaminergic system, the midbrain contains other cell types that may be involved in schizophrenia pathophysiology. The neurovascular hypothesis of schizophrenia postulates that both the neurovasculature structure and the functioning of the blood-brain barrier (BBB) are compromised in schizophrenia. In the present study, potential alteration in the BBB of patients with schizophrenia was investigated by single-nucleus RNA sequencing of post-mortem midbrain tissue (15 schizophrenia cases and 14 matched controls). We did not identify changes in the relative abundance of the major BBB cell types, nor in the sub-populations, associated with schizophrenia. However, we identified 14 differentially expressed genes in the cells of the BBB in schizophrenia as compared to controls, including genes that have previously been related to schizophrenia, such as FOXP2 and PDE4D. These transcriptional changes were limited to the ependymal cells and pericytes, suggesting that the cells of the BBB are not broadly affected in schizophrenia.

Identification of potential biomarkers and their correlation with immune infiltration cells in schizophrenia using combinative bioinformatics strategy

Many studies have identified changes in gene expression in brains of schizophrenia patients and their altered molecular processes, but the findings in different datasets were inconsistent and diverse. Here we performed the most comprehensive analysis of gene expression patterns to explore the underlying mechanisms and the potential biomarkers for early diagnosis in schizophrenia. We focused on 10 gene expression datasets in post-mortem human brain samples of schizophrenia downloaded from gene expression omnibus (GEO) database using the integrated bioinformatics analyses including robust rank aggregation (RRA) algorithm, Weighted gene co-expression network analysis (WGCNA) and CIBERSORT. Machine learning algorithm was used to construct the risk prediction model for early diagnosis of schizophrenia. We identified 15 key genes (SLC1A3, AQP4, GJA1, ALDH1L1, SOX9, SLC4A4, EGR1, NOTCH2, PVALB, ID4, ABCG2, METTL7A, ARC, F3 and EMX2) in schizophrenia by performing multiple bioinformatics analysis algorithms. Moreover, the interesting part of the study is that there is a correlation between the expression of hub genes and the immune infiltrating cells estimated by CIBERSORT. Besides, the risk prediction model was constructed by using both these genes and the immune cells with a high accuracy of 0.83 in the training set, and achieved a high AUC of 0.77 for the test set. Our study identified several potential biomarkers for diagnosis of SCZ based on multiple bioinformatics algorithms, and the constructed risk prediction model using these biomarkers achieved high accuracy. The results provide evidence for an improved understanding of the molecular mechanism of schizophrenia.

P551. Modelling of P300 and P50 Paradigms in the BSNIP Dataset Indicate Loss of NMDAR Function in Psychosis

Modelling of EEG during mismatch negativity, 40 Hz auditory steady state response and rest indicated consistently reduced excitability of pyramidal cells in schizophrenia (Adams et al, 2021, Biol Psych). Two potential explanations are i) hypofunction of pyramidal NMDA receptors, and ii) greater pyramidal inhibition by inhibitory interneurons. We disambiguated these hypotheses using a dynamic causal model (DCM) in which NMDA receptors and interneuronal inhibition are explicitly parameterised, and P300 and P50 EEG paradigms from the BSNIP dataset.

Comprehensive analyses of RNA-seq and genome-wide data point to enrichment of neuronal cell type subsets in neuropsychiatric disorders

Neurological and psychiatric disorders, including substance use disorders, share a range of symptoms, which could be the result of shared genetic background. Many genetic loci have been identified for these disorders using genome-wide association studies, but conclusive evidence about cell types wherein these loci are active is lacking. We aimed to uncover implicated brain cell types in neuropsychiatric traits and to assess consistency in results across RNA datasets and methods. We therefore comprehensively employed cell type enrichment methods by integrating single-cell transcriptomic data from mouse brain regions with an unprecedented dataset of 42 human genome-wide association study results of neuropsychiatric, substance use and behavioral/quantitative brain-related traits (n = 12,544,007 individuals). Single-cell transcriptomic datasets from the Karolinska Institute and 10x Genomics were used. Cell type enrichment was determined using Linkage Disequilibrium Score Regression, Multi-marker Analysis of GenoMic Annotation, and Data-driven Expression Prioritized Integration for Complex Traits. We found the largest degree of consistency across methods for implication of pyramidal cells in schizophrenia and cognitive performance. For other phenotypes, such as bipolar disorder, two methods implicated the same cell types, i.e., medium spiny neurons and pyramidal cells. For autism spectrum disorders and anorexia nervosa, no consistency in implicated cell types was observed across methods. We found no evidence for astrocytes being consistently implicated in neuropsychiatric traits. In conclusion, we provide comprehensive evidence for a subset of neuronal cell types being consistently implicated in several, but not all psychiatric disorders, while non-neuronal cell types seem less implicated.

A characterization of the molecular phenotype and inflammatory response of schizophrenia patient-derived microglia-like cells

Different lines of evidence support a causal role for microglia in the pathogenesis of schizophrenia. However, how schizophrenia patient-derived microglia are affected at the phenotypic and functional level is still largely unknown. We used a recently described model to induce patient-derived microglia-like cells and used this to analyze changes in the molecular phenotype and function of myeloid cells in schizophrenia. We isolated monocytes from twenty recent-onset schizophrenia patients and twenty non-psychiatric controls. We cultured the cells towards an induced microglia-like phenotype (iMG), analyzed the phenotype of the cells by RNA sequencing and mass cytometry, and their response to LPS. Mass cytometry showed a high heterogeneity of iMG in cells derived from patients as well as controls. The prevalence of two iMG clusters was significantly higher in schizophrenia patients (adjusted p-value < 0.001). These subsets are characterized by expression of ApoE, Ccr2, CD18, CD44, and CD95, as well as IRF8, P2Y12, Cx3cr1 and HLA-DR. In addition, we found that patient-derived iMG show an enhanced response to LPS, with increased secretion of TNF-α. Further studies are needed to replicate these findings, to determine whether similar subclusters are present in schizophrenia patients in vivo, and to address how these subclusters are related to the increased response to LPS, as well as other microglial functions.

Emerging Developments in Human Induced Pluripotent Stem Cell-Derived Microglia: Implications for Modelling Psychiatric Disorders With a Neurodevelopmental Origin.

Microglia, the resident tissue macrophages of the brain, are increasingly implicated in the pathophysiology of psychiatric disorders with a neurodevelopmental origin, including schizophrenia. To date, however, our understanding of the potential role for these cells in schizophrenia has been informed by studies of aged post-mortem samples, low resolution in vivo neuroimaging and rodent models. Whilst these have provided important insights, including signs of the heterogeneous nature of microglia, we currently lack a validated human in vitro system to characterize microglia in the context of brain health and disease during neurodevelopment. Primarily, this reflects a lack of access to human primary tissue during developmental stages. In this review, we first describe microglia, including their ontogeny and heterogeneity and consider their role in brain development. We then provide an evaluation of the potential for differentiating microglia from human induced pluripotent stem cells (hiPSCs) as a robust in vitro human model system to study these cells. We find the majority of protocols for hiPSC-derived microglia generate cells characteristically similar to foetal stage microglia when exposed to neuronal environment-like cues. This may represent a robust and relevant model for the study of cellular and molecular mechanisms in schizophrenia. Each protocol however, provides unique benefits as well as shortcomings, highlighting the need for context-dependent protocol choice and cross-lab collaboration and communication to identify the most robust and translatable microglia model.

Th17 and MAIT cell mediated inflammation in antipsychotic free schizophrenia patients

The immune hypothesis of schizophrenia has gained significant popularity in recent years in schizophrenia research. Evidence suggests that the peripheral immune system communicates with central nervous system and the effect propagates through microglial and lymphocyte crosstalk, especially during neuro-inflammation. Although, there is previous literature indicating changes in lymphocyte population in schizophrenia, detailed studies with respect to T and B cells are scarce. Mucosal associated invariant T (MAIT) cells are functionally associated with the gut microbiome. The gut microbiome has been implicated in the pathogenesis of schizophrenia. However, there is no information on the frequency of MAIT cells in schizophrenia. Hence, we investigated changes in proportions of T cells, B cells and MAIT cells in peripheral blood mononuclear cells derived from antipsychotic-free patients with schizophrenia in comparison to healthy controls. In line with earlier reports, we noted perturbations in Th17 cells. This study for the first time reports changes in frequencies of MAIT cells in a homogenous population of antipsychotic-free patients with schizophrenia. These changes, though not common across all patients nevertheless point to the fact that inflammation is prevalent in a significant subset of schizophrenia cases.

Expression of CB1-5HT2A receptor heteromers in olfactory neuroepithelium-derived cells in schizophrenia: Clinical and neuropsychological correlates

Expression of CB1-5HT2A receptor heteromers in olfactory neuroepithelium-derived cells in schizophrenia: Clinical and neuropsychological correlates

Effects on Glial Cell Glycolysis in Schizophrenia: An Advanced Aging Phenotype?

Schizophrenia is a severe and debilitating psychiatric disorder believed to have neurodevelopmental origins. Several studies have associated energy metabolism dysfunction with the disorder, mostly related to glycolysis alterations. Glucose is the obligatory energy substrate of the brain and glycolysis is the first step for its metabolism. This takes place predominantly in glial cells, astrocytes and oligodendrocytes, whereas neurons present a predominant oxidative profile. Thus, glial cells generate either lactate or pyruvate to neurons for ATP production. In addition, some aspects of schizophrenia may reflect an advanced aging phenotype with effects on various neural cell types at different stages of the disease. Given the role of glial cells in brain energy metabolism, the association of glycolysis dysfunction and the accelerated aging of neuronal cells in schizophrenia, studies focusing on those aspects can yield important insights into the causes and implications of the disorder. In turn, this may lead to novel therapeutic strategies for improved treatment of individuals suffering with this disorder.

18.1 MITOCHONDRIAL ALTERATIONS WITHIN THE PYRAMIDAL-PARVALBUMIN CELL MICROCIRCUIT IN THE PREFRONTAL CORTEX IN SCHIZOPHRENIA

BackgroundWorking memory, a core cognitive function impaired in schizophrenia, depends upon gamma oscillatory neuronal activity in the prefrontal cortex (PFC). Accordingly, individuals with schizophrenia show lower power of gamma oscillations in the PFC during tasks that involve working memory. Gamma oscillations emerge from the fast and coordinated activity of layer 3 excitatory pyramidal cells and inhibitory parvalbumin (PV) cells. As such, gamma oscillations have a particularly high energetic demand that is met by ATP production via oxidative phosphorylation (OXPHOS) within pyramidal and PV cell mitochondria. PFC layer 3 pyramidal cells have prominent reductions in OXPHOS-related gene pathways in schizophrenia. Importantly, OXPHOS can be regulated by two distinct processes: ATP demand to support neuronal firing, or upstream deficits in OXPHOS enzyme expression. Layer- and cell type-specific transcriptomic analyses of OXPHOS enzymes and ultrastructural analyses of mitochondrial morphology can help to distinguish between these two possibilities. Reduced ATP demand due to reduced neuronal firing is associated with 1) correlated expression levels of OXPHOS enzyme complexes, 2) lower expression of all subunits comprising Complex IV, the terminal and rate-limiting OXPHOS enzyme complex, and 3) normal mitochondrial morphology. Defective OXPHOS results in 1) elimination of correlated expression of OXPHOS enzyme complexes, 2) variable and inconsistent effects on Complex IV subunit expression, and 3) abnormal mitochondrial morphology.To determine which upstream factor is likely operative in the illness, we quantified OXPHOS enzyme complex transcripts in layer 3 pyramidal and PV cells, and performed ultrastructural analyses of mitochondrial morphology within pyramidal and PV axon boutons in layer 3 of the PFC in schizophrenia and unaffected comparison subjects.MethodsFor mRNA analyses, frozen tissue sections of area 9 from 36 pairs of schizophrenia and comparison subjects were stained for Nissl substance to identify pyramidal cells, or labeled using immunoperoxidase for aggrecan to identify PV cells. Layer 3 pyramidal and PV somata were dissected using laser capture microdissection. Transcriptome profiling was performed by microarray using Affymetrix GeneChips. Analysis of Complexes I, IV, and V expression in each neuronal population was assessed at q<0.05 in covariate- and multiple comparisons-corrected analyses.Electron microscopic analyses were performed in area 46 of 2 matched pairs of schizophrenia and comparison subjects. Mitochondria in pyramidal and PV cell boutons were classified as normal or abnormal using established criteria. Chi-square analysis was used to examine whether the percentages of each type differed between groups.ResultsThe expression of subunits comprising Complexes I, IV, and V in layer 3 pyramidal and PV cells was significantly lower in subjects with schizophrenia relative to unaffected comparison subjects. In both cell populations, expression of Complexes I, IV, and V were correlated (r=0.8-0.9) in unaffected comparison and schizophrenia subjects. Complex IV subunits showed 11–26% reductions in pyramidal cells, and 7-31% reductions in PV cells in schizophrenia. In both unaffected comparison and schizophrenia subjects, ≥99% of mitochondria in pyramidal cell boutons and ≥97% of mitochondria in PV cell boutons exhibited normal morphology.DiscussionThe current findings are most consistent with the interpretation that lower measures of OXPHOS in schizophrenia reflect lower demand for ATP production due to less neuronal firing.

S10. ASTROGLIAL PATHOLOGY IN SCHIZOPHRENIA: A META-ANALYSIS OF MRS STUDIES OF ANTERIOR CINGULATE MYOINOSITOL

BackgroundSeveral lines of evidence support a role for astroglial pathology in schizophrenia. 1H-MRS does not specifically differentiate between brain cell types; nevertheless, given that myo-inositol (mIns) is particularly abundant in astroglia rather than neuron and microglial cells, it can be considered an astroglial marker. mIns levels in the brain can decrease after brain injury with an efflux of mIns from astrocytes occurring as an osmoregulatory response. Many small sized studies have reported on mIns concentration in schizophrenia, but to date these have not been pooled to estimate a collective effect size. Examining the state of mIns deficit is a critical step to delineate the role of astroglial cells in schizophrenia. We conducted a meta-analysis to investigate the aberrations in myo-inositol levels in the ACC of patients with schizophrenia and measured using magnetic resonance spectroscopy (MRS).MethodsMedline, Google Scholar, Ovid Online and EMBASE databases were searched for studies published until September 2017. Search terms included full forms and variations of magnetic resonance spectroscopy, MRS, schizophrenia, psychosis, myo-inositol, inositol, Ins, mI, mIns. We included all 1H-MRS studies reporting mIns values for patients satisfying DSM or ICD based criteria for a primary psychotic disorder (SCZ) in comparison to a healthy controls (HC) group. We screened all identified abstracts, filtered studies that did not satisfy inclusion criteria, hand-searched references and contacted experts to locate further studies. 9 studies were identified that included 223 patients in SCZ group and 231 HCs. We excluded studies that reported only on comorbid illnesses, did not compare patients and HCs, or failed to report data required to construct effect size metrics. A random-effects and fixed-effects, inverse-weighted variance model was used to calculate the pooled effect size. Mean values were extracted and verified independently and effect sizes were computed based on Excel Macro produced by Major Depressive Disorder Neuroimaging Database (MaND) investigators.ResultsContrary to our expectations, in SCZ, there were no significant differences in ACC mIns in patients compared to HC (RFX=0.359, p= 0.057; 95% CI, -0.728 to 0.011; heterogeneity p = 0.0004). In the SCZ group, the mean effect size (Cohen’s d) was d= 0.39, indicating a medium sized difference. There were several methodological issues in the reported studies. Notably, most studies reported on mIns spectrum only when seeking differences in other metabolites; voxel placements were not standardized across the published studies; majority of patients were medicated, in various stages of illness. There was no statistical evidence for a publication bias (p=0.8).DiscussionThere is a medium effect-size, albeit statistically insignificant, reduction in the concentration of mIns in the anterior cingulate cortex in patients with schizophrenia. Given that mIns is the most readily accessible cortical marker in vivo for astroglial activity, it may be feasible to use MRS to stratify patients with astroglial abnormality from those without such an abnormality in schizophrenia.

Characterization of macrophages from schizophrenia patients

Genetic, epidemiological and post mortem studies have described an association between schizophrenia (SCZ) and the immune system. Microglia, the tissue-resident macrophages of the brain, not only play an essential role in inflammatory processes, but also in neurodevelopment and synapse refinement. It has therefore been hypothesized that aberrant functioning of these myeloid immune cells is involved in SCZ pathogenesis. Until now cellular research into the role of myeloid cells in SCZ has been limited to monocytes and functional assays are lacking. In this study we used monocyte-derived macrophages (mo-MΦs) as a model for macrophages and microglia in the CNS and examined two main functions: Inflammatory responses and expression and regulation of synapse refinement molecules. The expression of 24 genes involved in these key functions was assessed. Mo-MΦs were generated from 15 SCZ patients and 15 healthy controls. The cells were exposed to pro-inflammatory and anti-inflammatory stimuli (LPS, R848, IL-4 and dexamethasone), and the response was measured by qPCR and ELISA analyses. One of the genes of interest, P2RX7 that is associated with psychiatric diseases, was significantly reduced in expression after LPS stimulation in SCZ patients. None of the other assessed characteristics were different in this functional screen between mo-MΦs from SCZ patients compared to controls. Although these data suggest that overall the function of macrophages in SCZ is not impaired, further studies with larger groups that enable the possibility to study clinical subgroups and perform additional screenings to asses the full phenotype of the mo-MΦs are needed to strengthen this conclusion.

Altered Expression of ARP2/3 Complex Signaling Pathway Genes in Prefrontal Layer 3 Pyramidal Cells in Schizophrenia.

Lower dendritic spine density on layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) appears to contribute to cognitive dysfunction in schizophrenia, whereas psychosis is associated with excessive dopamine release in the striatum. These findings may be related via excitatory projections from the DLPFC to the ventral mesencephalon, the location of dopamine cells projecting to the striatum. Consistent with this hypothesis, deletion of the actin-related protein-2/3 (ARP2/3) complex, which regulates the actin cytoskeleton supporting dendritic spines, produced spine loss in cortical pyramidal cells and striatal hyperdopaminergia in mice. The authors sought to determine whether the ARP2/3 complex is altered in schizophrenia. In matched pairs of schizophrenia and comparison subjects, transcript levels of ARP2/3 complex signaling pathway were assessed in laser-microdissected DLPFC layer 3 and 5 pyramidal cells and layer 3 parvalbumin interneurons, and in total DLPFC gray matter. Transcript levels of ARP2/3 complex subunits and of nucleation promotion factors that regulate the ARP2/3 complex were significantly lower in DLPFC layer 3 and 5 pyramidal cells in schizophrenia. In contrast, these transcripts were unaltered, or only modestly changed, in parvalbumin interneurons and DLPFC gray matter. Down-regulation of the ARP2/3 complex signaling pathway, a common final pathway for multiple signaling cascades that regulate the actin cytoskeleton, would compromise the structural stability of spines, leading to their loss. In concert with findings from deletion of the ARP2/3 complex in mice, these findings support the idea that spine deficits in the DLPFC may contribute to subcortical hyperdopaminergia in schizophrenia.

Reduced number of peripheral natural killer cells in schizophrenia but not in bipolar disorder

Overwhelming evidence indicates that subthreshold inflammatory state might be implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BPD). It has been reported that both groups of patients might be characterized by abnormal lymphocyte counts. However, little is known about alterations in lymphocyte proportions that may differentiate SCZ and BPD patients. Therefore, in this study we investigated blood cell proportions quantified by means of microarray expression deconvolution using publicly available data from SCZ and BPD patients. We found significantly lower counts of natural killer (NK) cells in drug-naïve and medicated SCZ patients compared to healthy controls across all datasets. In one dataset from SCZ patients, there were no significant differences in the number of NK cells between acutely relapsed and remitted SCZ patients. No significant difference in the number of NK cells between BPD patients and healthy controls was observed in all datasets. Our results indicate that SCZ patients, but not BPD patients, might be characterized by reduced counts of NK cells. Future studies looking at lymphocyte counts in SCZ should combine the analysis of data obtained using computational deconvolution and flow cytometry techniques.

Reciprocal Alterations in Regulator of G Protein Signaling 4 and microRNA16 in Schizophrenia.

N-methyl-d-aspartate receptor (NMDAR) hypofunction in the dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathology of schizophrenia. NMDAR activity is negatively regulated by some G protein-coupled receptors (GPCRs). Signaling through these GPCRs is reduced by Regulator of G protein Signaling 4 (RGS4). Thus, lower levels of RGS4 would enhance GPCR-mediated reductions in NMDAR activity and could contribute to NMDAR hypofunction in schizophrenia. In this study, we quantified RGS4 mRNA and protein levels at several levels of resolution in the DLPFC from subjects with schizophrenia and matched healthy comparison subjects. To investigate molecular mechanisms that could contribute to altered RGS4 levels, we quantified levels of small noncoding RNAs, known as microRNAs (miRs), which regulate RGS4 mRNA integrity after transcription. RGS4 mRNA and protein levels were significantly lower in schizophrenia subjects and were positively correlated across all subjects. The RGS4 mRNA deficit was present in pyramidal neurons of DLPFC layers 3 and 5 of the schizophrenia subjects. In contrast, levels of miR16 were significantly higher in the DLPFC of schizophrenia subjects, and higher miR16 levels predicted lower RGS4 mRNA levels. These findings provide convergent evidence of lower RGS4 mRNA and protein levels in schizophrenia that may result from increased expression of miR16. Given the role of RGS4 in regulating GPCRs, and consequently the strength of NMDAR signaling, these findings could contribute to the molecular substrate for NMDAR hypofunction in DLPFC pyramidal cells in schizophrenia.

Altered Expression of CDC42 Signaling Pathway Components in Cortical Layer 3 Pyramidal Cells in Schizophrenia

BackgroundCognitive dysfunction in schizophrenia is associated with a lower density of dendritic spines on deep layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC). These alterations appear to reflect dysregulation of the actin cytoskeleton required for spine formation and maintenance. Consistent with this idea, altered expression of genes in the cell division cycle 42 (CDC42)-CDC42 effector protein (CDC42EP) signaling pathway, a key organizer of the actin cytoskeleton, was previously reported in DLPFC gray matter from subjects with schizophrenia. We examined the integrity of the CDC42-p21-activated serine/threonine protein kinases (PAK)-LIM domain-containing serine/threonine protein kinases (LIMK) signaling pathway in schizophrenia in a layer-specific and cell type–specific fashion in DLPFC deep layer 3. MethodsUsing laser microdissection, samples of DLPFC deep layer 3 were collected from 56 matched pairs of subjects with schizophrenia and comparison subjects, and levels of CDC42-PAK-LIMK pathway messenger RNAs were measured by quantitative polymerase chain reaction. These same transcripts also were quantified by microarray in samples of individually microdissected deep layer 3 pyramidal cells from a subset of the same subjects and from monkeys exposed to antipsychotics. ResultsRelative to comparison subjects, CDC42EP4, LIMK1, LIMK2, ARHGDIA, and PAK3 messenger RNA levels were significantly upregulated in subjects with schizophrenia in laminar and cellular samples. In contrast, CDC42 and PAK1 messenger RNA levels were significantly downregulated specifically in deep layer 3 pyramidal cells. These differences were not attributable to psychotropic medications or other comorbid factors. ConclusionsFindings from the present and prior studies converge on synergistic alterations in CDC42 signaling pathway that could destabilize actin dynamics and produce spine deficits preferentially in deep layer 3 pyramidal cells in schizophrenia.

Increased Interleukin-17 and decreased BAFF serum levels in drug-free acute schizophrenia

Hypotheses regarding an immune-cytokine basis of schizophrenia have been postulated with controversial findings and a lack of data related to many cytokines. The aim of this study was to assess serum levels of Interferon-γ (IFN-γ), Interleukin-4 (IL-4), Transforming Growth Factor-β (TGF-β), Interleukin-17 (IL-17) and B-cell Activating Factor (BAFF) in schizophrenic patients and to determine correlations between cytokine levels and clinical parameters. Serum cytokine levels were measured with ELISA techniques in 60 neuroleptic-free patients on acute phase of the disease (BPRS≥40) and 28 healthy controls matched for age and sex. Current symptoms were assessed with Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS). No significant difference was found between patients and controls regarding IFN-γ serum levels. IL-4 was not detected in both groups. Patients exhibited significantly higher IL-17 and lower BAFF serum levels. IL-17 and BAFF levels were negatively correlated in schizophrenic patients. SANS global score was negatively correlated with IL-17 and positively correlated with IFN-γ serum levels. These results argue against the involvement of Th1 or Th2 population cells in schizophrenia. IL-17 and BAFF could be valuable markers for schizophrenia.

Reduced microglial immunoreactivity for endogenous NMDA receptor agonist quinolinic acid in the hippocampus of schizophrenia patients.

Postmortem and positron emission tomography studies have indicated the pathophysiological involvement of microglial cells in schizophrenia. We hypothesized that the microglial production of quinolinic acid (QUIN), an endogenous N-methyl-d-aspartate receptor (NMDAR) agonist, may be linked to the previously described glutamatergic deficits in the hippocampus of schizophrenia patients. We performed a semi-quantitative assessment of QUIN-immunoreactive microglial cells in schizophrenia patients and matched controls in the CA1, CA2/3, and dentate gyrus (DG) area of the posterior hippocampal formation. Complementary immunostaining of the commonly used microglial surface marker HLA-DR was performed in adjacent histological sections. Fewer QUIN-immunoreactive microglial cells were observed in the CA1 hippocampal subregion of schizophrenia patients compared to controls (left p=0.028, right p=0.018). No significant diagnosis-dependent changes were observed in the CA2/3 and DG regions. These results were controlled for potential confounds by age, duration of disease, autolysis time, psychotropic medication, and hippocampal volume. No diagnosis-related differences were observed for the overall density of microglial cells (HLA-DR expression). Our findings suggest that reduced microglial QUIN content in the hippocampal CA1 region is associated with schizophrenia. We hypothesize that this association may contribute to impaired glutamatergic neurotransmission in the hippocampus of schizophrenia patients.