Postmortem Schizophrenia Brain Research Articles

Reported race-associated differences in control and schizophrenia post-mortem brain transcriptomes implicate stress-related and neuroimmune pathways.

The molecular mechanisms underlying racial disparities in schizophrenia (SCZ) illness courses and outcomes are poorly understood. While these differences are thought to arise partly through stressful social gradients, little is known about how these differences are reflected in the brain, nor how they might underlie disparate psychiatric outcomes. To better understand the neuro-molecular correlates of social gradients, SCZ, and their overlap, we analyzed post-mortem dorsolateral prefrontal cortex (DLPFC) RNAseq data from two racially diverse cohorts in the CommonMind Consortium (235 reported Black and 546 White, 322 SCZ cases and 459 controls) using differential expression and gene set variation analyses. We observed differences in brain gene expression that were consistent across cohorts and reported race. A combined mega-analysis identified 1,514 genes with differential expression (DE) between reported race groups after accounting for diagnosis and other covariates. Functional enrichment analyses identified upregulation of genes involved in stress and immune response, highlighting the potential role of environmental differences between reported race groups. In a race-by-diagnosis interaction analysis, no individual genes passed statistical significance. However, 109 gene sets showed statistically significant differences, implicating metabolic and immune pathways. Our results suggest molecular mechanisms uniquely perturbed across reported race groups and identify several candidate pathways associated with SCZ in a reported race-dependent manner. Our results underscore the importance of diverse cohort ascertainment to better capture population-level differences in SCZ pathogenesis.

Gene Enrichment Analysis of Astrocyte Subtypes in Psychiatric Disorders and Psychotropic Medication Datasets.

Astrocytes have many important functions in the brain, but their roles in psychiatric disorders and their responses to psychotropic medications are still being elucidated. Here, we used gene enrichment analysis to assess the relationships between different astrocyte subtypes, psychiatric diseases, and psychotropic medications (antipsychotics, antidepressants and mood stabilizers). We also carried out qPCR analyses and “look-up” studies to assess the chronic effects of these drugs on astrocyte marker gene expression. Our bioinformatic analysis identified gene enrichment of different astrocyte subtypes in psychiatric disorders. The highest level of enrichment was found in schizophrenia, supporting a role for astrocytes in this disorder. We also found differential enrichment of astrocyte subtypes associated with specific biological processes, highlighting the complex responses of astrocytes under pathological conditions. Enrichment of protein phosphorylation in astrocytes and disease was confirmed by biochemical analysis. Analysis of LINCS chemical perturbagen gene signatures also found that kinase inhibitors were highly discordant with astrocyte-SCZ associated gene signatures. However, we found that common gene enrichment of different psychotropic medications and astrocyte subtypes was limited. These results were confirmed by “look-up” studies and qPCR analysis, which also reported little effect of psychotropic medications on common astrocyte marker gene expression, suggesting that astrocytes are not a primary target of these medications. Conversely, antipsychotic medication does affect astrocyte gene marker expression in postmortem schizophrenia brain tissue, supporting specific astrocyte responses in different pathological conditions. Overall, this study provides a unique view of astrocyte subtypes and the effect of medications on astrocytes in disease, which will contribute to our understanding of their role in psychiatric disorders and offers insights into targeting astrocytes therapeutically.

A glimpse on the architecture of hnRNP C1/C2 interaction network in cultured oligodendrocytes

hnRNP represent a large family of RNA-binding proteins related to regulation of transcriptional and translational processes. More specifically, hnRNPs play pivotal roles in the myelination of the central nervous system. The regulation of these proteins are associated with neurodegenerative and psychiatric disorders, including schizophrenia. hnRNPs were shown differentially regulated on schizophrenia postmortem brain tissue as well as in cultured oligodendrocytes treated with clozapine, a common antipsychotic used in schizophrenia treatment. Here we employed co-immunoprecipitation of hnRNP C1/C2 to investigate for the first time in a large-scale manner its interaction partners on cultured oligodendrocytes (MO3.13). Even preliminarily, results bring a more comprehensive description of hnRNP C1/C2 interaction network, and therefore insights regarding the potential role of this protein in the central nervous system in health and disease, warranting further investigation.

Mitochondrial dysfunction in schizophrenia: With a focus on postmortem studies

Among the many brain abnormalities in schizophrenia are those related to mitochondrial functions such as oxidative stress, energy metabolism and synaptic efficacy. The aim of this paper is to provide a brief review of mitochondrial structure and function and then to present abnormalities in mitochondria in postmortem brain in schizophrenia with a focus on anatomy. Deficits in expression of various mitochondrial genes have been found in multiple schizophrenia cohorts. Decreased activity of complexes I and IV are prominent as well as abnormal levels of individual subunits that comprise the complexes of the electron transport chain. Ultrastructural studies have shown layer, input and cell specific decreases in mitochondria. In cortex, there are fewer mitochondria in axon terminals, neuronal somata of pyramidal neurons and oligodendrocytes in both grey and white matter. In the caudate and putamen mitochondrial number is linked with symptoms and symptom severity. While there is a decrease in the number of mitochondria in astrocytes, mitochondria are smaller in oligodendrocytes. In the nucleus accumbens and substantia nigra, mitochondria are similar in density, size and structural integrity in schizophrenia compared to controls. Mitochondrial production of ATP and calcium buffering are essential in maintaining synaptic strength and abnormalities in these processes could lead to decreased metabolism and defective synaptic activity. Abnormalities in mitochondria in oligodendrocytes might contribute to myelin pathology and underlie dysconnectivity in the brain. In schizophrenia, mitochondria are affected differentially depending on the brain region, cell type in which they reside, subcellular location, treatment status, treatment response and predominant symptoms.

Ultrastructural evidence for glutamatergic dysregulation in schizophrenia

The aim of this paper is to summarize ultrastructural evidence for glutamatergic dysregulation in several linked regions in postmortem schizophrenia brain. Following a brief summary of glutamate circuitry and how synapses are identified at the electron microscopic (EM) level, we will review EM pathology in the cortex and basal ganglia. We will include the effects of antipsychotic drugs and the relation of treatment response. We will discuss how these findings support or confirm other postmortem findings as well as imaging results. Briefly, synaptic and mitochondrial density in anterior cingulate cortex was decreased in schizophrenia, versus normal controls (NCs), in a selective layer specific pattern. In dorsal striatum, increases in excitatory synaptic density were detected in caudate matrix, a compartment associated with cognitive and motor function, and in the putamen patches, a region associated with limbic function and in the core of the nucleus accumbens. Patients who were treatment resistant or untreated had significantly elevated numbers of excitatory synapses in limbic striatal areas in comparison to NCs and responders. Protein levels of vGLUT2, found in subcortical glutamatergic neurons, were increased in the nucleus accumbens in schizophrenia. At the EM level, schizophrenia subjects had an increase in density of excitatory synapses in several areas of the basal ganglia. In the substantia nigra, the protein levels of vGLUT2 were elevated in untreated patients compared to NCs. The density of inhibitory synapses was decreased in schizophrenia versus NCs. In schizophrenia, glutamatergic synapses are differentially affected depending on the brain region, treatment status, and treatment response.

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

Although circular RNAs (circRNAs) are enriched in the mammalian brain, very little is known about their potential involvement in brain function and psychiatric disease. Here, we show that circHomer1a, a neuronal-enriched circRNA abundantly expressed in the frontal cortex, derived from Homer protein homolog 1 (HOMER1), is significantly reduced in both the prefrontal cortex (PFC) and induced pluripotent stem cell-derived neuronal cultures from patients with schizophrenia (SCZ) and bipolar disorder (BD). Moreover, alterations in circHomer1a were positively associated with the age of onset of SCZ in both the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). No correlations between the age of onset of SCZ and linear HOMER1 mRNA were observed, whose expression was mostly unaltered in BD and SCZ postmortem brain. Using in vivo circRNA-specific knockdown of circHomer1a in mouse PFC, we show that it modulates the expression of numerous alternative mRNA transcripts from genes involved in synaptic plasticity and psychiatric disease. Intriguingly, in vivo circHomer1a knockdown in mouse OFC resulted in specific deficits in OFC-mediated cognitive flexibility. Lastly, we demonstrate that the neuronal RNA-binding protein HuD binds to circHomer1a and can influence its synaptic expression in the frontal cortex. Collectively, our data uncover a novel psychiatric disease-associated circRNA that regulates synaptic gene expression and cognitive flexibility.

IPSC-derived homogeneous populations of developing schizophrenia cortical interneurons have compromised mitochondrial function.

Schizophrenia (SCZ) is a neurodevelopmental disorder. Thus, studying pathogenetic mechanisms underlying SCZ requires studying the development of brain cells. Cortical interneurons (cINs) are consistently observed to be abnormal in SCZ postmortem brains. These abnormalities may explain altered gamma oscillation and cognitive function in patients with SCZ. Of note, currently used antipsychotic drugs ameliorate psychosis, but they are not very effective in reversing cognitive deficits. Characterizing mechanisms of SCZ pathogenesis, especially related to cognitive deficits, may lead to improved treatments. We generated homogeneous populations of developing cINs from 15 healthy control (HC) iPSC lines and 15 SCZ iPSC lines. SCZ cINs, but not SCZ glutamatergic neurons, show dysregulated Oxidative Phosphorylation (OxPhos) related gene expression, accompanied by compromised mitochondrial function. The OxPhos deficit in cINs could be reversed by Alpha Lipoic Acid/Acetyl-L-Carnitine (ALA/ALC) but not by other chemicals previously identified as increasing mitochondrial function. The restoration of mitochondrial function by ALA/ALC was accompanied by a reversal of arborization deficits in SCZ cINs. OxPhos abnormality, even in the absence of any circuit environment with other neuronal subtypes, appears to be an intrinsic deficit in SCZ cINs.

Gene Expression Profiles Associated with Brain Aging are Altered in Schizophrenia

Existence of aging associated transcriptional differences in the schizophrenia brain was investigated in RNA sequencing data from 610 postmortem Dorso-Lateral Pre-Frontal Cortex (DLPFC) samples in the CommondMind Consortium (CMC) and the psychENCODE cohorts. This analysis discovered that the trajectory of gene expression changes that occur during brain aging differed between schizophrenia cases and unaffected controls. Mainly, the identified gene expression differences between the diagnosis groups shrank in magnitude following 60 years of age. A differential expression analysis restricted to the 40 to 60 year age group identified 556 statistically significant loci that replicated and had highly consistent gene expression fold changes in the two cohorts. An interaction between age and diagnosis in the wider psychENCODE cohort was also detected. Gene set enrichment analysis discovered disruptions in mitochondria, RNA splicing and phosphoprotein gene pathways. The identified differentially expressed genes in the two cohorts were also significantly enriched in genomic regions associated with schizophrenia although no enrichment was observed for differentially expressed genes identified in the 40 to 60 year age group. This work implicates disruptions to the normal brain aging processes in the pathology of schizophrenia and demonstrates the need for age stratification in schizophrenia postmortem brain gene expression studies.

Chromosomal Conformations and Epigenomic Regulation in Schizophrenia.

Chromosomal conformations, including promoter-enhancer loops, provide a critical regulatory layer for the transcriptional machinery. Therefore, schizophrenia, a common psychiatric disorder associated with broad changes in neuronal gene expression in prefrontal cortex and other brain regions implicated in psychosis, could be associated with alterations in higher-order chromatin. Here, we review early studies on spatial genome organization in the schizophrenia postmortem brain and discuss how integrative approaches using cell culture and animal model systems could gain deeper insight into the potential roles of higher-order chromatin for the neurobiology of and novel treatment avenues for common psychiatric disease.

A novel methodology to evaluate the molecular validity of preclinical psychosis models compared to schizophrenia brain pathology

Rodent models of schizophrenia (SCZ) are indispensable when screening for novel treatments, but quantifying their translational relevance with the underlying human pathophysiology has proved difficult. A novel systems methodology (shown in Figure 1) was developed integrating and comparing proteomic data of anterior prefrontal cortex tissue from SCZ post-mortem brains and matched controls with data obtained from four established glutamatergic rodent models, with the aim of evaluating which of these models represent SCZ most closely. Liquid chromatography coupled tandem mass spectrometry (LC-MSE) proteomic profiling was applied comparing healthy and “disease state” in human post-mortem samples and rodent brain tissue samples. Protein-protein interaction networks were constructed from significant abundance changes and enrichment analyses enabled the identification of pathophysiological characteristics of the disorder, which were represented across all four rodent models. Subsequently, these functional domains were used for cross-species comparisons. Five functional domains such as “development and differentiation” represented across all four rodent models, were identified. It was quantified that the chronic phencyclidine (cPCP) model represented SCZ brain changes most closely for four of these functional domains, by using machine-learning techniques. This is the first study aiming to quantify which rodent model recapitulates the neuropathological features of SCZ most closely. The methodology and findings presented here support recent efforts to overcome translational hurdles of preclinical psychiatric research by associating behavioural endophenotypes with distinct biological processes.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Peptidomic analysis of the anterior temporal lobe and corpus callosum from schizophrenia patients

Schizophrenia is a complex disorder hypothesized to develop from a combination of genetic, neurodevelopmental, and environmental factors. Molecules that are directly involved in the pathogenesis of schizophrenia and may serve as biomarker candidates can be identified with “omics” approaches such as proteomics and peptidomics. In this context, we performed a peptidomic study in schizophrenia postmortem brains, to our knowledge the first such study in schizophrenia patients. We investigated the anterior temporal lobe (ATL) and corpus callosum (CC) by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and a label-free ion quantification technique based on data-dependent acquisition (DDA). Results indicated alterations in a specific intracellular neurogranin peptide in both the ATL and CC and a decrease of PepH, a fragment of histone H2B type 1-H intracellular peptide, in the ATL. PepH was tested in serum-deprived Neuro2A cells and showed a protective effect against cell death. Cells were also challenged with lipopolysaccharide (LPS), and PepH was able to prevent the endotoxic effects of LPS. Our data suggest that specific intracellular peptides are altered in schizophrenia patients. The potential biological activity of PepH supports intracellular peptides as novel targets in the study not only of schizophrenia but also of other neuropsychiatric diseases. Biological significancePsychiatric disorders are considerably more difficult to diagnose in their early stages. Usually, by the time the diagnosis is clear and clinical treatment can be started, the disorder is already established and thus of greater severity. Consequently, the scientific community has been searching for biomarker candidates that can aid the early detection of such disorders and for novel therapeutics to improve treatment or at least delay disease progression. Moreover, key molecules involved in the establishment of psychiatric diseases may help the understanding of their pathogenesis and thus drive the development of more effective treatments. The present work screened peptides that might be possible novel targets to control cell machinery in schizophrenia and identified an intracellular peptide with potential cytoprotective activity. To our knowledge, this is the first peptidomic study in schizophrenia patients.

Differential proteome and phosphoproteome may impact cell signaling in the corpus callosum of schizophrenia patients

Schizophrenia is a multifactorial disease in both clinical and molecular terms. Thus, depicting the molecular aspects of the disease will contribute to the understanding of its biochemical mechanisms and consequently may lead to the development of new treatment strategies. The protein phosphorylation/dephosphorylation switch acts as the main mechanism for regulating cellular signaling. Moreover, approximately onethird of human proteins are phosphorylable. Thus, identifying proteins differentially phosphorylated in schizophrenia postmortem brains may improve our understanding of the molecular basis of brain function in this disease. Hence, we quantified the phosphoproteome of corpus callosum samples collected post mortem from schizophrenia patients and healthy controls. We used state-of-the-art, bottom-up shotgun mass spectrometry in a two-dimensional liquid chromatography-tandem mass spectrometry setup in the MSE mode with label-free quantification. We identified 60,634 peptides, belonging to 3283 proteins. Of these, 68 proteins were differentially phosphorylated, and 56 were differentially expressed.These proteins are mostly involved in signaling pathways, such as ephrin B and ciliary neurotrophic factor signaling. The data presented here are novel because this was the very first phosphoproteome analysis of schizophrenia brains. They support the important role of glial cells, especially astrocytes, in schizophrenia and help to further the understanding of the molecular aspects of this disease. Our findings indicate a need for further studies on cell signaling, which might shape the development of treatment strategies.

Possibility of a sex-specific role for a genetic variant in FRMPD4 in schizophrenia, but not cognitive function.

The neurotransmitter disturbances responsible for cognitive dysfunction in schizophrenia are hypothesized to originate with alterations in postsynaptic scaffold proteins. We have recently reported that protein levels of FRMPD4, a multiscaffolding protein that modulates both Homer1 and postsynaptic density protein 95 activity, is altered in the schizophrenia postmortem brain, in regions involved in cognition. Here, we set out to investigate whether genetic variation in FRMPD4 is associated with cognitive function in people with schizophrenia. We selected and examined a novel single nucleotide polymorphism, rs5979717 (positioned in the noncoding 3' untranslated region of FRMPD4 and potentially influencing protein expression), for its association with schizophrenia and nine measures of cognitive function, using age-matched and sex-matched samples from 268 schizophrenia cases and 268 healthy controls. Brain samples from 20 schizophrenia patients and 20 healthy controls were additionally genotyped to study the influence of this variant on protein expression of FRMPD4. Allelic distribution of rs5979717 was associated with schizophrenia in females (χ=4.52, P=0.030). No effects of rs5979717 were observed on cognitive performance, nor an influence of rs5979717 genotypes on the expression of FRMPD4 proteins in postmortem brain samples. These data provide initial support for a sex-specific role for common variation in rs5979717 in schizophrenia, which now warrants further investigation.

Pioneering ambient mass spectrometry imaging in psychiatry: Potential for new insights into schizophrenia

Understanding the molecular basis of schizophrenia is essential for disease management, and several molecular biology tools have been employed for this purpose. Mass spectrometry, which is used mostly in proteomic and metabolomic studies, is one such tool. Here, we present the first psychiatric study to use mass spectrometry imaging (MSI) with desorption electrospray ionization (DESI). Preparation of samples for use with DESI-MSI is remarkably simple and quick and preserves the spatial distribution of analytes. By using this tool, we found differences in the phospholipid content in schizophrenia postmortem brains. These results validate both the role of phospholipids in schizophrenia and the value of this MS tool in furthering the understanding of the molecular aspects of the disease.

Metabotropic glutamate receptor 5, and its trafficking molecules Norbin and Tamalin, are increased in the CA1 hippocampal region of subjects with schizophrenia

Metabotropic glutamate receptor 5 (mGluR5) is involved in hippocampal-dependent learning and memory, which are processes disrupted in schizophrenia. Recent evidence from human genetic and animal studies suggests that the regulation of mGluR5, including its interaction with trafficking molecules, may be altered in the disorder. However there have been no investigations of hippocampal mGluR5 or mGluR5 trafficking molecules in the postmortem schizophrenia brain to confirm this. In the present study, we investigated whether protein expression of mGluR5, as well as Norbin and Tamalin (modulators of mGluR5 signalling and trafficking), might be altered in the schizophrenia brain, using postmortem samples from the hippocampal CA1 region of schizophrenia subjects and matched controls (n=20/group). Protein levels of mGluR5 (total: 42%, p<0.001; monomer: 25%, p=0.011; dimer: 52%, p<0.001) and mGluR5 trafficking molecules (Norbin: 47%, p<0.001; Tamalin: 34%, p=0.009) were significantly higher in schizophrenia subjects compared to controls. To determine any influence of antipsychotic drug treatment, all proteins were also correlated with lifetime chlorpromazine equivalents in patients, and separately measured in the hippocampus of rats exposed to haloperidol or olanzapine treatment. mGluR5 was negatively correlated with lifetime antipsychotic drug exposure in schizophrenia patients, suggesting antipsychotic drugs could reduce mGluR5 protein in schizophrenia subjects. In contrast, mGluR5 and mGluR5 trafficking molecules were not altered in the hippocampus of antipsychotic drug treated rats. This investigation provides strong support for the hypothesis that mGluR5 is involved in the pathology of schizophrenia, and that alterations to mGluR5 trafficking might contribute to the hippocampal-dependent cognitive dysfunctions associated with this disorder.

Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation.

Knockout of genes encoding metabotropic glutamate receptor 5 (mGluR5) or its endogenous regulators, such as Norbin, induce a schizophrenia-like phenotype in rodents, suggesting dysregulation of mGluR5 in schizophrenia. Human genetic and pharmacological animal studies support this hypothesis, but no studies have explored mGluR5 dysfunction at the molecular level in the postmortem schizophrenia brain. We assessed mGluR5 mRNA and protein levels in the dorsolateral prefrontal cortex (DLPFC) using a large cohort of schizophrenia and control subjects (n = 37/group), and additionally measured protein levels of recently discovered mGluR5 endogenous regulators, Norbin (neurochondrin), Tamalin (GRASP-1), and Preso1 (FRMPD4), which regulate mGluR5 localization, internalization and signaling. While mGluR5 mRNA expression was unchanged, mGluR5 protein levels were significantly higher in schizophrenia subjects compared to controls (total: +22%; dimer: +54%; p < 0.001). Conversely, mGluR5 regulatory proteins were expressed at lower levels in schizophrenia subjects compared to controls (Norbin -37%, p < 0.001; Tamalin -30%, p = 0.084; Preso1 -29%, p = 0.001). mGluR5 protein was significantly associated with mGluR5 mRNA and mGluR5 endogenous regulators in control subjects, but these associations were lost in schizophrenia subjects. Lastly, there were no associations between protein measures and lifetime antipsychotic history in schizophrenia subjects. To confirm no antipsychotic influence, all proteins were measured in the prefrontal cortex of rats exposed to haloperidol or olanzapine; there were no effects of antipsychotic drug treatment on mGluR5, Norbin, Tamalin or Preso1. The results from our study provide compelling evidence that mGluR5 regulation is altered in schizophrenia, likely contributing to the altered glutamatergic signaling that is associated with the disorder.

Cyclin-Dependent Kinase 5 Regulates Dendritic Spine Formation and Maintenance of Cortical Neuron in the Mouse Brain.

Cyclin-dependent kinase 5 (Cdk5) activity is dependent on its association with 1 of 2 neuron-specific activators, p35 or p39. Cdk5 and its activators play an important role in brain development as well as higher functions like synaptic plasticity, learning, and memory. Reduction in p35 was reported in postmortem schizophrenia brain, in which reduced dendritic spine density was observed. Previous in vitro experiments have shown that Cdk5 is involved in dendritic spine formation, although in vivo evidence is limited. We examined dendritic spine formation in inducible-p35 conditional knockout (p35 cKO); p39 KO mice. When we deleted the p35 gene either during early postnatal days or at adult stage, we observed reduced spine densities of layer V neurons in the cerebral cortex and CA1 pyramidal neurons in the hippocampus. We further generated CA1-specific p35 conditional knockout (CA1-p35 cKO) mice and also CA1-p35 cKO; p39 KO mice in which have specific deletion of p35 in the CA1 region of hippocampus. We found a greater reduction in spine densities in CA1 pyramidal neurons in CA1-p35 cKO; p39 KO mice than in CA1-p35 cKO mice. These results indicate that dendritic spine formation and neuronal maintenance are dependent on Cdk5 activity.

FADD adaptor and PEA-15/ERK1/2 partners in major depression and schizophrenia postmortem brains: Basal contents and effects of psychotropic treatments

Enhanced brain apoptosis (neurons and glia) may be involved in major depression (MD) and schizophrenia (SZ), mainly through the activation of the intrinsic (mitochondrial) apoptotic pathway. In the extrinsic death pathway, pro-apoptotic Fas-associated death domain (FADD) adaptor and its non-apoptotic p-Ser194 FADD form have critical roles interacting with other death regulators such as phosphoprotein enriched in astrocytes of 15kDa (PEA-15) and extracellular signal-regulated kinase (ERK). The basal status of FADD (protein and messenger RNA (mRNA)) and the effects of psychotropic drugs (detected in blood/urine samples) were first assessed in postmortem prefrontal cortex of MD and SZ subjects (including a non-MD/SZ suicide group). In MD, p-FADD, but not total FADD (and mRNA), was increased (26%, n=24; all MD subjects) as well as p-FADD/FADD ratio (a pro-survival marker) in antidepressant-free MD subjects (50%, n=10). In contrast, cortical FADD (and mRNA), p-FADD, and p-FADD/FADD were not altered in SZ brains (n=21) regardless of antipsychotic medications (except enhanced mRNA in treated subjects). Similar negative results were quantified in the non-MD/SZ suicide group. In MD, the regulation of multifunctional PEA-15 (i.e., p-Ser116 PEA-15 blocks pro-apoptotic FADD and PEA-15 prevents pro-survival ERK action) and the modulation of p-ERK1/2 were also investigated. Cortical p-PEA-15 was not changed whereas PEA-15 was increased mainly in antidepressant-treated subjects (16–20%). Interestingly, cortical p-ERK1/2/ERK1/2 ratio was reduced (33%) in antidepressant-free when compared to antidepressant-treated MD subjects. The neurochemical adaptations of brain FADD (increased p-FADD and pro-survival p-FADD/FADD ratio), as well as its interaction with PEA-15, could play a major role to counteract the known activation of the mitochondrial apoptotic pathway in MD.

Early developmental disturbances of cortical inhibitory neurons: contribution to cognitive deficits in schizophrenia.

Cognitive dysfunction is a disabling and core feature of schizophrenia. Cognitive impairments have been linked to disturbances in inhibitory (gamma-aminobutyric acid [GABA]) neurons in the prefrontal cortex. Cognitive deficits are present well before the onset of psychotic symptoms and have been detected in early childhood with developmental delays reported during the first year of life. These data suggest that the pathogenetic process that produces dysfunction of prefrontal GABA neurons in schizophrenia may be related to altered prenatal development. Interestingly, adult postmortem schizophrenia brain tissue studies have provided evidence consistent with a disease process that affects different stages of prenatal development of specific subpopulations of prefrontal GABA neurons. Prenatal ontogeny (ie, birth, proliferation, migration, and phenotypic specification) of distinct subpopulations of cortical GABA neurons is differentially regulated by a host of transcription factors, chemokine receptors, and other molecular markers. In this review article, we propose a strategy to investigate how alterations in the expression of these developmental regulators of subpopulations of cortical GABA neurons may contribute to the pathogenesis of cortical GABA neuron dysfunction and consequently cognitive impairments in schizophrenia.

Rethinking metabotropic glutamate receptor 5 pathological findings in psychiatric disorders: implications for the future of novel therapeutics

BackgroundPharmacological modulation of metabotropic glutamate receptor 5 (mGluR5) is of marked interest as a novel therapeutic mechanism to treat schizophrenia and major depression. However, the status of mGluR5 in the pathophysiology of these disorders remains unknown.DiscussionThe majority of studies in the schizophrenia post-mortem brain indicate that total mGluR5 expression is unaltered. However, close examination of the literature suggests that these findings are superficial, and in actuality, a number of critical factors have not yet been considered; alterations may be highly dependent on brain region, neuronal population or molecular organisation in specific cellular compartments. A number of genetic knockout studies (mGluR5, Norbin, Homer1 etc.) continue to lend support to a role of mGluR5 in the pathology of schizophrenia, providing impetus to explore the regulation of mGluR5 beyond total mGluR5 protein and mRNA levels. With regards to major depression, preliminary evidence to date shows a reduction in total mGluR5 protein and mRNA levels; however, as in schizophrenia, there are no studies examining mGluR5 function or regulation in the pathological state. A comprehensive understanding of mGluR5 regulation in major depression, particularly in comparison to schizophrenia, is crucial as this has extensive implications for mGluR5 targeting novel therapeutics, especially considering that opposing modulation of mGluR5 is of therapeutic interest for these two disorders.SummaryDespite the complexities, examinations of post-mortem human brain provide valuable insights into the pathologies of these inherently human disorders. It is important, especially with regards to the identification of novel therapeutic drug targets, to have an in depth understanding of the pathophysiologies of these disorders. We posit that brain region- and cell type-specific alterations exist in mGluR5 in schizophrenia and depression, with evidence pointing towards altered regulation of this receptor in psychiatric pathology. We consider the implications of these alterations, as well as the distinction between schizophrenia and depression, in the context of novel mGluR5 based therapeutics.