Project description:The dorsolateral prefrontal cortex (DLPFC) is the association area in the anterior part of the frontal lobe and has a crucial role in cognitive functioning and negative symptoms in SZschizophrenia. However, limited information of altered protein networks is available in this region in schizophrenia. We performed a proteomic analysis using single-shot liquid chromatography-tandem mass spectrometry of grey matter of postmortem DLPFC in chronic schizophrenia subjects (n=20) and healthy individuals (n=20) followed by bioinformatic analysis to identify altered protein networks in SZ.
Project description:Alterations of synaptic function in individuals with schizophrenia have been found in transcriptomics, proteomics, and genome wide association studies. Impaired synaptic glutamatergic (excitatory) and GABAergic (inhibitory) neurotransmission in affected brain regions (e.g. dorsolateral prefrontal cortex; DLPFC) is thought to be involved in the core symptoms of schizophrenia. However, there are no quantitative measurements of synaptic function in the human DLPFC, therefore concrete and specific functional alterations of voltage gated ion channels of glutamate and GABA receptors are lacking. We have begun to address this problem by directly measuring AMPA- and GABA receptor-mediated synaptic currents in postmortem brains from subjects with schizophrenia and contrasting to controls. We demonstrate in our preliminary work that the function of synaptic receptors is maintained in postmortem brains and is significantly decreased in schizophrenia compared to controls. Our overarching hypothesis is that reductions in both inhibitory and excitatory currents underlie synaptic deficits in schizophrenia. We will test rigor and reproducibility of this hypothesis in independent case-control cohorts. These deficits in synaptic currents can be statistically modeled with transcriptomic data which will be useful in downstream studies that pharmacologically challenge activation of these currents.
Project description:Fresh frozen post mortem prefrontal cortex tissue (Brodman area 46) was obtained from 44 individuals varying in age from 0 to 49 years. RNA was extracted from these samples and hybridized to HG133plus2.0 GeneChips. The data was used to examine patterns of gene expression over the course of human postnatal developmental and ageing. PMI - postmortem interval, DLPFC - dorsolateral prefrontal cortex Experiment Overall Design: The dataset consists of 44 individuals varying in age from 0 to 49 years
Project description:Schizophrenia is associated with alterations in working memory that reflect dysfunction of dorsolateral prefrontal cortex (DLPFC) circuitry. Working memory depends on the activity of excitatory pyramidal cells in DLPFC layer 3, and to a lesser extent in layer 5. Although many studies have profiled gene expression in DLPFC gray matter in schizophrenia, little is known about cell type-specific transcript expression in these two populations of pyramidal cells. We hypothesized that interrogating gene expression specifically in DLPFC layer 3 or 5 pyramidal cells would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness.
Project description:Fresh frozen post mortem prefrontal cortex tissue (Brodman area 46) was obtained from 44 individuals varying in age from 0 to 49 years. RNA was extracted from these samples and hybridized to HG133plus2.0 GeneChips. The data was used to examine patterns of gene expression over the course of human postnatal developmental and ageing. PMI - postmortem interval, DLPFC - dorsolateral prefrontal cortex
Project description:Schizophrenia is associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction is manifest as cognitive deficits that appear to arise from disturbances in gamma frequency oscillations. These oscillations are generated in DLPFC layer 3 via reciprocal connections between pyramidal cells and parvalbumin (PV)-containing interneurons. The density of cortical PV neurons is not altered in schizophrenia, but expression levels of several transcripts involved in PV cell function, including PV, are lower in the disease.
Project description:Impairments in certain cognitive processes (e.g., working memory) are typically most pronounced in schizophrenia (SZ), intermediate in bipolar disorder (BP) and least in major depressive disorder (MDD). Given that working memory depends, in part, on neural circuitry that includes pyramidal neurons in layer 3 (L3) and layer 5 (L5) of the dorsolateral prefrontal cortex (DLPFC), we sought to determine if transcriptome alterations in these neurons were shared or distinctive for each diagnosis.
Project description:Anorexia nervosa (AN), bulimia nervosa (BN), and obsessive-compulsive disorder (OCD) are complex psychiatric disorders with shared obsessive features, thought to arise from the interaction of multiple genes of small effect with environmental factors. Potential candidate genes for AN, BN, and OCD have been identified through clinical association and neuroimaging studies; however, recent genome-wide association studies of eating disorders (ED) so far have failed to report significant findings. Additionally, few if any studies have interrogated postmortem brain tissue for evidence of eQTLs associated with candidate genes, which has particular promise as an approach to elucidating molecular mechanisms of association. We therefore selected single nucleotide polymorphisms (SNPs) based on candidate gene studies for AN, BN, and OCD from the literature, and examined the association of these SNPs with gene expression across the lifespan in prefrontal cortex of a non-psychiatric control cohort (N=268). Several risk-predisposing SNPs were significantly associated with gene expression among control subjects. We then measured gene expression in the prefrontal cortex of cases previously diagnosed with obsessive psychiatric disorders, e.g., eating disorders (ED; N=15), and obsessive-compulsive disorder/obsessive-compulsive personality disorder or tics (OCD/OCPD/Tic; N=16), and non-psychiatric controls (N=102) and identified 6 and 286 genes that were differentially expressed between ED compared to controls and OCD cases compared to controls, respectively (FDR < 5%). However, none of the clinical risk SNPs were among the eQTLs and none were significantly associated with gene expression within the broad obsessive cohort, suggesting larger sample sizes or other brain regions may be required to identify candidate molecular mechanisms of clinical association in postmortem brain datasets. Gene expression data from the dorsolateral prefrontal cortex (DLPFC) from postmortem tissue on 133 subjects - 15 eating disorder (ED) patients, 16 obessive compulsive disorder (OCD) patients, and 102 non-psychiatric controls - run on the Illumina HumanHT-12 v3 microarray