Brpf1 knockdown reduces inhibitory neurotransmission and regulates gene expression of GABAergic interneurons derived from MGE
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ABSTRACT:
PROVIDER: PRJNA663318 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12637810_1.fastq.gz | Fastqsanger.gz | |||
| SRR12637810_2.fastq.gz | Fastqsanger.gz | |||
| SRR12637811_1.fastq.gz | Fastqsanger.gz | |||
| SRR12637811_2.fastq.gz | Fastqsanger.gz | |||
| SRR12637812_1.fastq.gz | Fastqsanger.gz |
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Project description:Our research is to investigate the role of Brpf1 in the development and function of GABAergic interneurons. To test this, we used mouse primary in vitro cultured GABAergic interneurons derived from medial ganglionic eminence (MGE) and utilized AAV-shBrpf1 virus to knockdown Brpf1. We performed mRNA-seq on the total RNA extracted from the infected neurons .We found that most of the up-regulated genes after Brpf1 knockdown were involved in processes such as protein binding, gene negative transcription, ubiquitination, and inflammation by mRNA-seq. We found that many genes related to neuronal calcium, potassium ion transport and neurotransmitter release changed after Brpf1 was knockdown.Our results demonstrate the key role of Brpf1 in related gene expression of GABAergic interneurons, and provide new lights on the underlying neurobiological mechanisms of BRPF1 mutations that cause mental retardation in children or adolescents.
2021-02-23 | GSE157903 | GEO
Project description:Intellectual disability is closely related to impaired GABA neurotransmission. Brpf1 was specifically expressed in medial ganglionic eminence (MGE), a developmental niche of GABAergic interneurons, and patients with BRPF1 mutations showed intellectual disability. To test its role in the development and function of MGE-derived GABAergic interneurons, we performed immunofluorescence staining, whole-cell patch-clamp, MGE transplantation, and mRNA-Seq to understand its effect on neuronal differentiation, dendritic morphology, electrophysiology, migration, and gene regulation, using mouse MGE-derived GABAergic interneurons infected with AAV-shBrpf1. The results showed that Brpf1 knockdown had a decreasing trend, although not significant, on the differentiation of GABAergic interneurons into parvalbumin+ interneurons. Moreover, increased firing threshold, decreased number of evoked action potentials, and a reduced amplitude of miniature inhibitory postsynaptic currents were observed before any significant change of MAP2+ dendritic morphology and in vivo migration ability appeared. Finally, mRNA-Seq analysis revealed that genes related to neurodevelopment and synaptic transmission such as Map2k7 were dysregulated. Our results demonstrated a key role of Brpf1 in inhibitory neurotransmission and related gene expression of GABAergic interneurons.
| S-EPMC8496217 | biostudies-literature
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.
2022-01-03 | PXD023551 | Pride
Project description:The Dlx homeodomain transcription factors are implicated in regulating the function of inhibitory GABAergic interneurons; therefore understanding their functions will provide insights into disorders such as epilepsy, mental retardation and autism. Identifying genes that are downstream of Dlx1/2 function and are relevant for the differentiation and survival of GABAergic interneurons. During embryonic development, cortical GABAergic interneurons are generated in the proliferative zone of the medial ganglionic eminence (MGE), from where they migrate to reach their final positions in the cortex. The differentiation of these interneuron precursors is dependent on Dlx genes, as shown by Dlx1/Dlx2 double mutants, which have a block in GABAergic cell differentiation and in cell migration. When interneuron progenitors are isolated from the mutant MGE and growth in culture, they are able to proceed along their differentiation program. However, mutant cells growth in vitro show defects in cell morphogenesis and increased cell apoptosis. We hypothesize that Dlx transcription factors regulate important aspects of GABAergic neuron differentiation such as the formation and growth of axon and dendrites, and the formation of inhibitory synapses. We generated E15.5 mouse embryos that are Dlx1/2 -/- or Dlx1/2 +/?. Genotype was confirmed by PCR. A total of 8 litters were used. For each experiment, we pooled tissue from at least 6 different embryos of the same genotype. We dissected the ventricular and subventricular zones of the MGE (rostral part). This area contains ~1 million of progenitor cells per embryo. We isolated total RNA using the Stratagene RNA Miniprep kit (these samples are called MGE+/ and MGE-/- in our proposal). In addition, we used the same area (ventricular and subventricular zones of the rostral MGE) to perform primary neuronal cultures. Cells were maintained 3 days in vitro. After that, we isolated total RNA using the Stratagene RNA Miniprep kit (samples called primary cells+/ and primary cells-/- in our proposal). We would like to perform gene expression comparison between: 1) MGE+/ and MGE-/-, and 2) primary cells+/ and primary cells-/-.
2008-06-16 | E-GEOD-8311 | biostudies-arrayexpress
Project description:We hypothesized that mouse Brpf1 plays critical roles in the morphology and function of hippocampal neurons, and its deficiency leads to learning and memory deficits. To test this, we performed immunofluorescence, whole-cell patch clamp, mRNA-Seq on shBrpf1 infected primary cultured hippocampal neurons to study the effect of Brpf1 knockdown on neuronal morphology, electrophysiological characteristics and gene regulation. In addition, we performed stereotactic injection into adult mouse hippocampus to knockdown Brpf1 in vivo and examined the learning and memory ability by Morris Water Maze. We found that mild knockdown of Brpf1 reduced mEPSC frequency of cultured hippocampal neurons, before any significant changes of dendritic morphology showed. We also found that hippocampal knockdown of Brpf1 reduced the learning and memory ability of mice to some extent. Finally, mRNA-Seq analyses showed that genes related to learning, memory, movement and synaptic transmission (such as C1ql1, Gpr17, Htr1d, Glra1, Cxcl10, Grin2a) were dysregulated upon Brpf1 knockdown. Our results showed that Brpf1 mild knockdown attenuated hippocampal excitatory neurotransmission and reduced learning and memory ability, which helps explain the symptoms of patients with BRPF1 mutations.
2021-05-19 | GSE174600 | GEO
Project description:Transplantation of GABAergic interneurons (INs) can sustain long-standing benefits in animal models of epilepsy and other neurological disorders. In a therapeutic perspective, a renewable source of functional GABAergic INs is needed. Here, we identified five factors (Foxg1, Sox2, Ascl1, Dlx5 and Lhx6) able to convert fibroblasts directly into induced GABAergic INs (iGABA-INs), displaying the molecular signature of telencephalic INs. The selected factors recapitulate in fibroblasts the activation of transcriptional networks required for the specification of GABAergic fate during telencephalon development. iGABA-INs exhibited progressively maturing firing patterns comparable to those of cortical INs, had synaptic currents and released GABA. Importantly, upon grafting in the hippocampus, iGABA-INs survived, matured and their optogenetic stimulation triggered GABAergic transmission and inhibited the activity of connected granule cells. The five factors also converted human cells into functional GABAergic neurons. These properties define iGABA-INs as a promising tool for disease modeling and cell-based therapeutic approaches. Comparison of iGABA-INs transcriptional profile with those of starting fibroblasts and GAD67-GFP+ cortical interneurons.
2015-12-15 | E-GEOD-74065 | biostudies-arrayexpress
Project description:During development, newborn interneurons migrate throughout the embryonic brain. Here, we provide evidence that these interneurons act in a paracrine fashion to regulate developmental oligodendrocyte formation. Specifically, we show that medial ganglionic eminence (MGE) interneurons secrete factors that promote genesis of oligodendrocytes from glially-biased cortical precursors in culture. Moreover, when MGE interneurons are genetically ablated in vivo prior to their migration, this causes a deficit in cortical oligodendrogenesis. Modeling of the interneuron-precursor paracrine interaction using transcriptome data identifies the cytokine fractalkine as responsible for the pro-oligodendrocyte effect in culture. This paracrine interaction is important in vivo, since knockdown of the fractalkine receptor CX3CR1 in embryonic cortical precursors, or constitutive knockout of CX3CR1 causes decreased numbers of oligodendrocyte progenitor cells (OPCs) and oligodendrocytes in the postnatal cortex. Thus, in addition to their role in regulating neuronal excitability, interneurons act in a paracrine fashion to promote the developmental genesis of oligodendrocytes. We used microarrays to generate a list of expressed genes in purified medial ganglionic eminence (MGE) interneurons
2017-03-06 | GSE95696 | GEO
Project description:Medial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+ and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical and physiological properties. However, the molecular mechanisms regulating their diversity remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates subtype-specific transcriptional regulation of gene expression in MGE-derived interneurons, leading to altered subtype identities. Notably, MGE-specific conditional Grin1 loss results in a systemic downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders, particularly schizophrenia. Our study hence provides a roadmap for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders.
2021-01-25 | GSE156201 | GEO
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.
2023-08-01 | GSE221994 | GEO
Project description:Interneurons are fundamental cells for maintaining the excitation-inhibition balance in the brain in health and disease. While interneurons have been shown to play a key role in the pathophysiology of autism spectrum disorder (ASD) in adult mice, little is known about how their maturation is altered in the developing striatum in ASD. Here, we aimed to track striatal developing interneurons and elucidate the molecular and physiological alterations in the Cntnap2 knockout mouse model. Using Stereo-seq and single-cell RNA sequencing data, we first characterized the pattern of expression of Cntnap2 in the adult brain and at embryonic stages in the medial ganglionic eminence (MGE), a transitory structure producing most cortical and striatal interneurons. We found that Cntnap2 is enriched in the striatum, compared to the cortex, particularly in the developing striatal cholinergic interneurons. We then revealed enhanced MGE-derived cell proliferation, followed by increased cell loss during the canonical window of developmental cell death in the Cntnap2 knockout mice. We uncovered specific cellular and molecular alterations in the developing Lhx6-expressing cholinergic interneurons of the striatum, which impacts interneuron firing properties during the first postnatal week. Overall, our work unveils some of the mechanisms underlying the shift in the developmental trajectory of striatal interneurons which greatly contribute to the ASD pathogenesis.
2023-01-12 | GSE222383 | GEO