A Co-Culture Model of Dopaminergic and Glutamatergic Neurons Derived from Patients with Idiopathic Schizophrenia reveals a Hypodopaminergic Phenotype
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE275064 | GEO | 2024/08/27
REPOSITORIES: GEO
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Project description:Whole-genome expression studies in peripheral tissues of patients affected by schizophrenia (SCZ) can provide new insights into the molecular basis of the disorder and innovative biomarkers that may be of great usefulness in the clinical practice. Recent evidence suggests that skin fibroblasts could represent a non-neural peripheral model useful to investigate molecular alterations in psychiatric disorders. A microarray expression study was conducted comparing transcriptomic profiles of skin fibroblasts from SCZ patients and controls. Fibroblasts can be more advantageous to discover mental disorder aetiological mechanisms since they seem more similar to neurons and less affected by the environmental confounders. Transcriptomic profiles of human skin fibroblasts obtained from 20 schizophrenia patients were compared to 20 controls
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Project description:Schizophrenia (SCZ) is a psychiatric disorder with a strong genetic determinant. A major hypothesis to explain disease aetiology comprises synaptic dysfunction associated with excitatory-inhibitory imbalance of synaptic transmission, ultimately contributing to impaired network oscillation and cognitive deficits associated with the disease. Here, we studied the morphological and functional properties of a highly defined co-culture of GABAergic and glutamatergic neurons derived from induced pluripotent stem cells (iPSC) from patients with idiopathic SCZ. Our results indicate upregulation of synaptic genes and increased excitatory synapse formation on GABAergic neurons in co-cultures. In parallel, we observed decreased lengths of axon initial segments, concordant with data from postmortem brains from patients with SCZ. Patch-clamp analyses revealed differential processing of excitatory input with markedly increased spontaneous excitatory postsynaptic currents (EPSC) recorded from GABAergic SCZ neurons and decreased spontaneous EPSC from glutamatergic SCZ neurons. Likewise, we observed decreased amplitudes of calcium signals selectively in GABAergic neurons while frequency was increased in both neuronal populations. Finally, MEA recordings from neuronal networks indicate increased synchronization of network activity. In conclusion, our results suggest selective deregulation of neuronal activity and synaptic transmission in SCZ samples, providing evidence for differential signal processing in GABAergic and glutamatergic neurons as a potential base for aberrant network synchronization.
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Project description:A Co-Culture Model of Dopaminergic and Glutamatergic Neurons Derived from Patients with Idiopathic Schizophrenia reveals a Hypodopaminergic Phenotype
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Project description:The epigenome of human brain cells encompasses key information in understanding brain function in both healthy and diseased states. To further explore this, we used ATAC-seq to profile chromatin structure in four distinct populations of cells (glutamatergic neurons, GABAergic neurons, oligodendrocytes, and microglia/astrocytes), from three different regions of the brain. Chromatin accessibility was found to vary vastly by cell type and, more moderately, by brain region, with glutamatergic neurons showing the greatest regional variability. Transcription factor footprinting pointed to cell-specific transcriptional regulators and inferred cell-specific regulation of protein coding genes, long intergenic noncoding RNAs, and microRNAs. In vivo transgenic mouse experiments validated the cell type specificity of a number of human-derived regulatory sequences. Open chromatin regions in glutamatergic neurons were enriched for neuropsychiatric risk variants, particularly those associated with schizophrenia. Combining differential chromatin accessibility analysis using ATAC-seq data from bulk tissue increased our statistical power to confirm glutamatergic neurons as the cell type most affected in schizophrenia. Jointly, these findings illustrate the utility of studying the cell type specific epigenome in complex tissues such as the human brain and implicate an association among chromatin accessibility in glutamatergic neurons and genetic risk for schizophrenia.
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Project description:Induced pluripotent stem cell (iPSC) technology presents a unique opportunity to model schizophrenia (SCZ) and other neuropsychiatric disorders in vitro by providing investigators with the means to grow patient-specific neurons. Three approaches are possible regarding disease modeling for a genetically heterogenous disorder, like SCZ. One is the draw subjects from the general patient population who have suspected but undefined disease-causing genetic variants. Another is to focus on a common phenotype, such as clinical presentation, response to medications or age of onset. The third is to use patients who have on a common genetic etiology. We have chosen the latter approach and are developing a library of iPSCs from patients with SCZ who harbor chromosome 22q11.2 microdeletions. In this preliminary study involving 4 patients and 4 controls, gene expression profiling was carried out on early differentiating neurons using RNA-seq. Several important observations were made. First, despite the dramatic molecular changes that occur during the reprogramming of a somatic cell into an iPSC, and its subsequent differentiation into neurons, processes that require months of cultivation with multiple changes in growth medium and treatment with a variety of growth factors, we show that 22q11.2 haploinsufficiency at the DNA level is recapitulated in vitro by substantial decreases in the expression of nearly every gene in the deleted region. Overall, transcriptome profiling revealed significant changes in the expression of 604 genes (423 increased in the SCZ samples, 181 decreased; >1.5-fold change, uncorrected p<0.05). Among the differentially expressed genes were a number of SCZ candidates and genes involved in retinoic acid (RA) signaling. In addition, there was some overlap with the differentially expressed genes found in another study using SCZ patients who do not have 22q11.2 del, one of which was CYP26A1, which codes for one of the major enzymes involved in RA metabolism. Although the sample size in this preliminary study is small, the findings support the idea that dysregulated RA-signaling could be a potential target for therapeutic intervention in SZ associated with 22q11.2 del, and perhaps other subgroups of patients. 4 controls and 4 patients
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Project description:Whole-genome expression studies in peripheral tissues of patients affected by schizophrenia (SCZ) can provide new insights into the molecular basis of the disorder and innovative biomarkers that may be of great usefulness in the clinical practice. Recent evidence suggests that skin fibroblasts could represent a non-neural peripheral model useful to investigate molecular alterations in psychiatric disorders. A microarray expression study was conducted comparing transcriptomic profiles of skin fibroblasts from SCZ patients and controls. Fibroblasts can be more advantageous to discover mental disorder aetiological mechanisms since they seem more similar to neurons and less affected by the environmental confounders.
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Project description:Total RNA sequencing for human induced pluripotent derived neurons organoids from healthy controls and schizophrenia (SCZ) patients
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Project description:From Stertz et al 2021 "Human-induced pluripotent stem cells (hiPSCs) allow for the establishment of brain cellular models of psychiatric disorders that account for a patient’s genetic background. Here, we conducted an RNA-sequencing profiling study of hiPSC-derived cell lines from schizophrenia (SCZ) subjects, most of which are from a multiplex family, from the population isolate of the Central Valley of Costa Rica. hiPSCs, neural precursor cells, and cortical neurons derived from six healthy controls and seven SCZ subjects were generated using standard methodology. Transcriptome from these cells was obtained using Illumina HiSeq 2500, and differential expression analyses were performed using DESeq2 (|fold change|>1.5 and false discovery rate < 0.3), in patients compared to controls. We identified 454 differentially expressed genes in hiPSC-derived neurons, enriched in pathways including phosphoinositide 3-kinase/glycogen synthase kinase 3 (PI3K/GSK3) signaling, with serum-glucocorticoid kinase 1 (SGK1), an inhibitor of glycogen synthase kinase 3β, as part of this pathway. We further found that pharmacological inhibition of downstream effectors of the PI3K/GSK3 pathway, SGK1 and GSK3, induced alterations in levels of neurite markers βIII tubulin and fibroblast growth factor 12, with differential effects in patients compared to controls. While demonstrating the utility of hiPSCs derived from multiplex families to identify significant cell-specific gene network alterations in SCZ, these studies support a role for disruption of PI3K/GSK3 signaling as a risk factor for SCZ." This dataset includes Samples from the manuscript "Convergent genomic and pharmacological evidence of PI3K/GSK3 signaling alterations in neurons from schizophrenia patients" by Stertz et al 2021 published in Neuropsychopharmacology.
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Project description:Genetic studies have suggested a role for glial pathology in the genesis of schizophrenia (SCZ). To assess the nature of SCZ-associated human glial dysfunction in vivo, we established human glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotential cells (hiPSCs), derived from patients with juvenile-onset schizophrenia or healthy controls. To this end, hiPSC GPCs were implanted neonatally into either immunodeficient myelin wild-type mice, in which donor GPCs remained as progenitors or became astrocytes, or into myelin-deficient shiverer mice, in which the GPCs also gave rise to oligodendrocytes. When implanted into shiverers, the SCZ-derived GPCs exhibited less expansion in the white matter than did control GPCs, instead migrating prematurely into the cortex. The SCZ GPC-transplanted shiverers were consequently hypomyelinated relative to control GPC-engrafted mice. When established instead in myelin wild-type hosts, the SCZ hiPSC glial chimeras manifested markedly delayed and diminished astrocytic differentiation, which was associated with diminished prepulse inhibition and an aberrant behavioral phenotype across multiple modalities. Accordingly, RNA-seq revealed significant differences in both glial differentiation-associated and synaptic gene expression by SCZ GPCs. These data suggest a potent contribution of cell-autonomous glial dysfunction to the development of schizophrenia, and provide a model for the in vivo assessment of human glial pathology in this disorder.
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Project description:Adults and children with the 22q11.2 deletion syndrome (22q11.2DS) demonstrate cognitive, social and emotional impairments and markedly increased risk for schizophrenia (SCZ). The alterations in early human brain development resulting from this deletion remain unclear. Here we use organoid models of the developing human cerebral cortex derived from patients with 22q11.2DS and SCZ as well as unaffected controls to identify cell-type-specific developmental abnormalities that result from this genomic lesion. Using RNA-sequencing and follow-up experimental validation we find that loss of genes within the 22q11.2 locus leads to delayed development of cortical neurons.
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