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Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development

ABSTRACT: Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development

PROVIDER: PRJNA763492 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15903000_1.fastq.gz	Fastqsanger.gz
	SRR15903000_2.fastq.gz	Fastqsanger.gz
	SRR15903001_1.fastq.gz	Fastqsanger.gz
	SRR15903001_2.fastq.gz	Fastqsanger.gz
	SRR15902995_1.fastq.gz	Fastqsanger.gz

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Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development

Project description:Genome binding/occupancy profiling was carried out by high throughput sequencing in human developmental cortical interneurons and developmental glutamatergic neurons derived from healthy control vs schizophrenia iPSCs

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Foxp1 regulates the development of glutamatergic synaptic input onto spiny projection neurons expressing Drd2 [snRNA-seq]

Project description:Long-range glutamatergic inputs from the cortex and thalamus provide important motor and cognitive information to the striatum where they are integrated for learning and action planning. Genetic programs and transcription factors that orchestrate the development of these inputs are relatively unknown. The transcription factor, FOXP1, is crucial for the development of spiny projection neurons (SPNs) in the striatum. We investigated the cell-specific role of Foxp1 in the formation of glutamatergic inputs – including corticostriatal inputs. Embryonic Foxp1 deletion in dopamine receptor 2-expressing SPNs (D2 Foxp1cKO) leads to reduced transmission of corticostriatal excitatory inputs and decreased synaptically driven excitability. Postnatal deletion of Foxp1 also resulted in decreased glutamatergic inputs onto D2 SPNs. Single nuclei RNA sequencing of D2 Foxp1cKO striatum identified downregulated postsynaptic genes, consistent with the synaptic phenotype. Reinstating Foxp1 postnatally rescued electrophysiological deficits and expression of a subset of genes that were altered by embryonic deletion in D2 SPNs. Postnatal Foxp1 reinstatement could also rescue behavioral phenotypes. In summary, we demonstrate that FOXP1 regulates the development of corticostriatal circuitry. Further, changes at multiple levels of brain function resulting from loss of Foxp1 are rescued with postnatal Foxp1 reinstatement, indicating a therapeutic approach for individuals with FOXP1 syndrome.

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LFQ proteomics of mouse GABAergic interneurons during traumatic brain injury

Project description:Unilateral Traumatic Brain Injury (TBI) causes functional disturbances of the neuronal networks spreading even to the undamaged cortical hemisphere. The phenomenon, referred to as transhemispheric diaschisis, is suggested to be mediated by an imbalance of the strength of glutamatergic, excitatory vs. GABAergic, inhibitory neurotransmission. Here we present evidence that a switch in expression of α Subunits of pore-forming L-Type voltage-gated calcium channels (VGCC), by an expression of CaV1.3 and simultaneous ablation of CaV1.2 in GABAergic interneurons could balance early cortical disturbances manifested as contralateral hyperexcitability in the early phase after TBI. The switch of the VGCC alpha Subunits in GABAergic interneurons was detected using the GAD67-GFP (Glutamate Decarboxylase 67 – Green Fluorescent Protein) Knock-in mouse line. Mice received a TBI with a Controlled Cortical Impact (CCI) to the primary motor and somatosensory cortex at postnatal day 19-21 under anesthesia in vivo. Single GFP+ interneurons located in the undamaged, contralateral cortex were isolated by Fluorescence-Activated Cell Sorting (FACS) and further analyzed by Mass Spectrometry (MS). The switch was associated with an increased excitability of Somatostatin (SST) interneurons and extracellular network activity in acute brain slices in Microelectrode Array (MEA) recordings, which could be restored in presence of isradipine (100 nM), which selectively blocks CaV1.3-containing VGCCs. These data suggest that a switch in alpha.subunits of VGCCs expressed on SST-positive interneurons stabilizes early hyperactivity of the contralateral cortical network at 72 h after TBI, thereby promoting an adaptive mechanism to counterbalance post-traumatic hyperexcitabilty that might lead to epileptogenesis.

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Foxp1 regulates the development of glutamatergic synaptic input onto spiny projection neurons expressing Drd2 [snRNA-seq]

Project description:Foxp1 regulates the development of glutamatergic synaptic input onto spiny projection neurons expressing Drd2 [snRNA-seq]

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Common schizophrenia risk variants are implicated in the function of glutamatergic neurons

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:Our group has reported that the histone methyltransferase DOT1L is necessary for proper cortical plate development and layer distribution of glutamatergic neurons, however, its specific role on cortical interneuron development has not yet been explored. Here, we demonstrate that DOT1L affects interneuron development in a cell-autonomous manner. Deletion of Dot1l in MGE-derived interneuron precursor cells results in an overall reduction and altered distribution of GABAergic interneurons in the cortical plate at postnatal day (P) 0. Furthermore, we observed an altered proportion of GABAergic interneurons in the cortex and striatum at P21 with a significant decrease in Parvalbumin (PVALB)-expressing interneurons. Altogether, our results indicate that reduced numbers of cortical interneurons upon DOT1L deletion results from altered postmitotic differentiation/maturation.

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Project description:We report changes in gene expression in schizophrenia developmental glutamatergic neurons by genome-wide transcriptome analysis.

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Genome-wide transcriptional analysis of human iPSC-derived healthy control vs. schizophrenia cortical interneurons

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