Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJDB10118 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DRR235131_1.fastq.gz | Fastqsanger.gz | |||
| DRR235131_2.fastq.gz | Fastqsanger.gz | |||
| DRR235132_1.fastq.gz | Fastqsanger.gz | |||
| DRR235132_2.fastq.gz | Fastqsanger.gz | |||
| DRR235133_1.fastq.gz | Fastqsanger.gz |
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Project description:SETD1A, a histone methyltransferase, is a key schizophrenia susceptibility gene. Mutant mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics, accompanied by specific deficits in working memory that recapitulates SCZ-related alterations. We show that Setd1a targets mostly enhancers and reveal a striking overlap between Setd1a and Mef2 chromatin targets. Setd1a targets are highly expressed in pyramidal neurons and enriched for genes with postnatally-biased expression involved in synaptic structure and function. Notably, evolutionary conserved Setd1a binding sites and target genes are strongly associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues working memory deficits. We identify LSD1 as a major demethylase counteracting the effects of Setd1a methyl transferase activity and show that LSD1 antagonism in adult Setd1a-deficient mice results in a full rescue of the behavioral abnormalities and axonal branching deficits. Our findings advance our understanding of how SETD1A mutations predispose to SCZ and point to therapeutic interventions.
2019-10-09 | GSE123652 | GEO
Project description:Large-scale genomic studies of schizophrenia implicate genes involved in the epigenetic regulation of transcription by histone methylation and genes encoding components of the synapse. However, the interactions between these pathways in conferring risk to psychiatric illness are unknown. Loss-of-function (LoF) mutations in the gene encoding histone methyltransferase, SETD1A, confer substantial risk to schizophrenia. Among several roles, SETD1A is thought to be involved in the development and function of neuronal circuits. Here, we employed a multi-omics approach to study the effects of heterozygous Setd1a LoF on gene expression and synaptic composition in mouse cortex across five developmental timepoints from embryonic day 14 to postnatal day 70. Using RNA sequencing, we observed that Setd1a LoF resulted in the consistent downregulation of genes enriched for mitochondrial pathways. This effect extended to the synaptosome, in which we found age-specific disruption to both mitochondrial and synaptic proteins. Using large-scale patient genomics data, we observed no enrichment for genetic association with schizophrenia within differentially expressed transcripts or proteins, suggesting they derive from a distinct mechanism of risk from that implicated by genomic studies. This study highlights biological pathways through which SETD1A loss-of-function may confer risk to schizophrenia. Further work is required to determine whether the effects observed in this model reflect human pathology.
2022-05-26 | PXD032742 | Pride
Project description:Using CRISPR/Cas9 to generate an hiPSC line with SETD1A haploinsufficiency and differentiating it into glutamatergic and GABAergic neurons, we found that SETD1A haploinsufficiency resulted in altered neuronal network activity, which was predominantly defined by increased network burst frequency, whereas unchanged global firing activity. In individual neurons, this network phenotype was reflected functionally by increased synchronized synaptic inputs and structurally by increased somatodendritic complexity in both glutamatergic and GABAergic neurons. The transcriptome profile in SETD1A haploinsufficient neurons demonstrated perturbations in gene sets associated with schizophrenia, synaptic transmission, and glutamatergic synaptic function. In addition, transcriptomic data suggested cAMP/PKA pathway might be disturbed in SETD1A haploinsufficient networks, which was further verified by pharmacological experiments.
2021-07-23 | GSE180648 | GEO
Project description:Schizophrenia (SCZ) is a chronic, serious mental disorder with severe burden on patients’ families and society. Although over 100 genes have been linked to SCZ pathogenies, the underlying molecular and cellular mechanisms remain largely unknown. Here, we generated a Setd1a haploinsufficiency mouse model to understand how this SCZ-associated epigenetic factor affects gene expression programs in cells of brain regions highly relevant to SCZ. By comparing single-cell RNA-seq results from wild type and Setd1a+/- mice, we found Setd1a heterozygosity causes highly diverse transcriptional adaptations across different cell types in prefrontal cortex and striatum, suggesting brain region- and cell type-specific mechanisms contribute to pathophysiology of SCZ. Interestingly, we found the Foxp2+ neurons exhibit the most prominent gene expression changes among the different neuron subtypes in PFC, which correlate with the H3K4me3 changes. Importantly, many of the genes dysregulated in heterozygous Setd1a mice are linked to neuron morphogenesis and synaptic function. Consistently, heterozygous Setd1a mice exhibit certain behavioral features of SCZ patients. Collectively, our study establishes Setd1a heterozygous mice as a model for understanding SCZ and uncovers a complex brain region- and cell type-specific changes that potentially underlying SCZ pathogenesis.
2022-01-12 | GSE181021 | GEO
Project description:Schizophrenia (SCZ) is a chronic, serious mental disorder with severe burden on patients’ families and society. Although over 100 genes have been linked to SCZ pathogenies, the underlying molecular and cellular mechanisms remain largely unknown. Here, we generated a Setd1a haploinsufficiency mouse model to understand how this SCZ-associated epigenetic factor affects gene expression programs in cells of brain regions highly relevant to SCZ. By comparing single-cell RNA-seq results from wild type and Setd1a+/- mice, we found Setd1a heterozygosity causes highly diverse transcriptional adaptations across different cell types in prefrontal cortex and striatum, suggesting brain region- and cell type-specific mechanisms contribute to pathophysiology of SCZ. Interestingly, we found the Foxp2+ neurons exhibit the most prominent gene expression changes among the different neuron subtypes in PFC, which correlate with the H3K4me3 changes. Importantly, many of the genes dysregulated in heterozygous Setd1a mice are linked to neuron morphogenesis and synaptic function. Consistently, heterozygous Setd1a mice exhibit certain behavioral features of SCZ patients. Collectively, our study establishes Setd1a heterozygous mice as a model for understanding SCZ and uncovers a complex brain region- and cell type-specific changes that potentially underlying SCZ pathogenesis.
2022-01-12 | GSE181025 | GEO
Project description:Schizophrenia (SCZ) is a chronic, serious mental disorder with severe burden on patients’ families and society. Although over 100 genes have been linked to SCZ pathogenies, the underlying molecular and cellular mechanisms remain largely unknown. Here, we generated a Setd1a haploinsufficiency mouse model to understand how this SCZ-associated epigenetic factor affects gene expression programs in cells of brain regions highly relevant to SCZ. By comparing single-cell RNA-seq results from wild type and Setd1a+/- mice, we found Setd1a heterozygosity causes highly diverse transcriptional adaptations across different cell types in prefrontal cortex and striatum, suggesting brain region- and cell type-specific mechanisms contribute to pathophysiology of SCZ. Interestingly, we found the Foxp2+ neurons exhibit the most prominent gene expression changes among the different neuron subtypes in PFC, which correlate with the H3K4me3 changes. Importantly, many of the genes dysregulated in heterozygous Setd1a mice are linked to neuron morphogenesis and synaptic function. Consistently, heterozygous Setd1a mice exhibit certain behavioral features of SCZ patients. Collectively, our study establishes Setd1a heterozygous mice as a model for understanding SCZ and uncovers a complex brain region- and cell type-specific changes that potentially underlying SCZ pathogenesis.
2022-01-12 | GSE181024 | GEO
Project description:Synaptic dysfunction represents a key pathophysiology in neurodevelopmental disorders such as autism spectrum disorder (ASD). Rare mutation R451C in human Neuroligin 3 (NLGN3, encoded by X-linked gene NLGN3), a cell adhesion molecule essential for synapse formation, has been linked to ASD. Despite success in recapitulating the social interaction behavioral deficits and the underlying synaptic abnormalities in mouse model, the impact of NLGN3 R451C on the human neuronal system remains elusive. Here, we generated isogenic knock-in human pluripotent stem cell lines harboring NLGN3 R451C allele and examined its impact on synaptic transmission. Analysis of co-cultured excitatory and inhibitory induced neurons (iNs) with mutation revealed an augmentation in excitatory synaptic strength comparing to isogenic control, but not in inhibitory synaptic transmission. Consistently, the augmentation in excitatory transmission was confirmed in iNs transplanted into mouse forebrain. Using single-cell RNA seq on co-cultured excitatory and inhibitory iNs, we identified differential expression genes (DEGs) and found NLGN3 R451C alters gene networks associated with synaptic transmission. Gene ontology and enrichment analysis revealed convergent gene networks associated with ASD and other mental disorders. Our finding suggests that the NLGN3 R451C mutation could preferentially impact excitatory neurons, which causes overall network properties changes and excitation-inhibition imbalance related to mental disorders.
2022-10-26 | GSE180751 | GEO
Project description:Background: The present study investigated a role of proteins from BET family (epigenetic readers) in schizophrenia-like abnormalities in MAM-E17 model of schizophrenia. Methods: An inhibitor of BET proteins, JQ1, was given during adolescence in postnatal days (P) 23-P30, and behavioral response (sensorimotor gating, recognition memory) and prefrontal cortex (mPFC) function (long-term potentiation (LTP), molecular and proteomic studies) were performed in adult males and females. Results: Deficits in sensorimotor gating and recognition memory were observed only in MAM-treated males. However, adolescent JQ1 treatment affected control, but MAM-treated groups in both sexes. Electrophysiological study showed an LTP impairment only in male MAM-treated animals, and JQ1 did not have any effect on LTP in the mPFC. In contrast, MAM did not affect immediate early gene expression (markers of neuronal and synaptic activity), but JQ1 altered them in both sexes. Proteomic study revealed alterations in MAM-treated groups only in males, while JQ1 affected both sexes. Conclusions: Prenatal MAM administration induced schizophrenia-like abnormalities only in males. In contrast, adolescent JQ1 treatment affected both sexes and induced behavioral changes in control groups, altered a markers of neuronal and synaptic activity and proteomic landscape in the mPFC of both groups (VEH- and MAM-treated). Thus, adolescent inhibition of BET family might change neuroplasticity in the mPFC.
2021-09-07 | PXD027050 | Pride
Project description:Among the fundamental unresolved questions in psychiatry is why symptoms of psychosis, such as auditory hallucinations in schizophrenia, fail to appear until early adulthood. Here we report that in mouse models of 22q11.2 deletion syndrome (22q11DS), a leading genetic cause of schizophrenia, synaptic transmission at thalamocortical inputs to the auditory cortex becomes disrupted later in life, thereby recapitulating the adult onset of psychosis. Age-dependent disruption of thalamocortical synaptic transmission in 22q11DS is mediated by dopamine receptor Drd2-targeting microRNA miR-338-3p, which is enriched in the thalamus but becomes depleted due to haploinsufficiency of the microRNA-processing 22q11DS gene Dgcr8. Deletion/knockdown of miR-338-3p causes the Drd2 increase in the auditory thalamus and abnormal sensitivity of 22q11DS thalamocortical inputs to antipsychotics, replicates auditory synaptic and behavioral abnormalities in 22q11DS, and eliminates age dependence of these auditory deficits. These results suggest that miR-338-3p mediates the pathogenic mechanism of 22q11DS-related psychosis and controls its late onset.
2016-10-10 | GSE73981 | GEO
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.
2023-03-20 | GSE224683 | GEO