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DLK-dependent protein network regulates hippocampal glutamatergic neuron degeneration

ABSTRACT: DLK-dependent protein network regulates hippocampal glutamatergic neuron degeneration

PROVIDER: PRJNA1108218 | ENA |

REPOSITORIES: ENA

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DLK-dependent protein network regulates hippocampal glutamatergic neuron degeneration

Project description:The conserved MAPKKK DLK plays many roles in neuronal development, axon injury, and neuronal stress responses. The outcomes of activating or inhibiting DLK signaling depend on cell-type and cellular contexts. Emerging evidence has implicated DLK signaling in several neurodegenerative diseases. However, our understanding of the DLK-dependent cellular network in the central nervous system remains limited. Here, we investigated roles of DLK in hippocampal glutamatergic neurons, using conditional knockout and overexpression mice. We find that dorsal CA1 and dentate gyrus neurons are particularly vulnerable to elevated DLK activity. We performed RiboTRAP-seq analysis and identified the DLK dependent translatome, majority of which are involved in neuronal developmental processes, neuronal stress responses, and synapse formation and function. Increasing DLK signaling is associated with disruptions of microtubules, potentially involving Stmn4. We also show that in primary hippocampal neurons DLK regulates neurite outgrowth, axon specification, and synapse formation. This study broadens our understanding of both conserved and cell-type specific effects of DLK signaling. The identification of translational targets of DLK in glutamatergic neurons has relevance to our understanding of neurodegenerative disease.

2025-01-16 | GSE266662 | GEO

Gene expression profiles of glutamatergic neuron progenitors (Neurod6-positive cells)

Project description:Gene expression profiles of glutamatergic neuron progenitors (Neurod6-positive cells)

2012-12-08 | E-MTAB-893 | biostudies-arrayexpress

Glutamatergic dysfunction precedes neuron loss in cerebral organoids with MAPT mutations

Project description:Glutamatergic dysfunction precedes neuron loss in cerebral organoids with MAPT mutations

| PRJNA719153 | ENA

Human NMDAR autoantibodies disrupt excitatory-inhibitory balance leading to hippocampal network hypersynchrony

Project description:Specific autoantibodies against the NMDA-receptor (NMDAR) GluN1 subunit cause severe and debilitating NMDAR-encephalitis. Autoantibodies induce prototypic disease symptoms resembling schizophrenia, including psychosis and cognitive dysfunction. Using a mouse passive transfer model applying human monoclonal anti-GluN1-autoantibodies, we observed CA1 pyramidal neuron hypoexcitability, reduced AMPA-receptor (AMPAR) signaling, and faster synaptic inhibition resulting in disrupted excitatory-inhibitory balance. Functional alterations were supported by widespread remodeling of the hippocampal proteome, including changes in glutamatergic and GABAergic neurotransmission. At the network level, anti-GluN1-autoantibodies amplified gamma oscillations and disrupted theta-gamma coupling. A data-informed network model revealed that lower AMPAR strength and faster GABAA-receptor current kinetics chiefly account for these abnormal oscillations. As predicted by our model and evidenced experimentally, positive allosteric modulation of AMPARs alleviated aberrant gamma activity and thus reinforced the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-hypofunction-induced aberrant synaptic, cellular, and network dynamics provide new mechanistic insights into disease symptoms in NMDAR-encephalitis and schizophrenia.

2023-09-24 | PXD032055 | Pride

Chromatin Immunoprecipitation analysis of mouse hippocampal neuron HT22 cells

Project description:Chromatin Immunoprecipitation analysis of mouse hippocampal neuron HT22 cells

| PRJNA720695 | ENA

A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation

Project description:The isocortex and hippocampal formation (HPF) in the mammalian brain play critical roles in perception, cognition, emotion and learning. We profiled ~1.3 million cells covering the entire adult mouse isocortex and HPF and derived a transcriptomic celltype taxonomy which includes many new glutamatergic and GABAergic neuron types. Contrary to the traditional view of HPF as having a simpler cellular organization, we discover a complete set of glutamatergic types in HPF homologous to all major subclasses found in the six-layered isocortex, suggesting that HPF and isocortex share a common circuit organization. We also identify large-scale continuous and graded variation of cell types along isocortical depth, across isocortical sheet and in multiple dimensions in hippocampus and subiculum. Overall, our study establishes a molecular architecture of mammalian isocortex and hippocampal formation and begins to shed light on its underlying relationship with the development, evolution, connectivity and function of these two brain structures.

2021-10-20 | GSE185862 | GEO

Dichotomic hippocampal transcriptome after glutamatergic versus GABAergic deletion of the cannabinoid CB1 receptor

Project description:Dichotomic hippocampal transcriptome after glutamatergic versus GABAergic deletion of the cannabinoid CB1 receptor

| PRJNA714401 | ENA

Glutamatergic dysfunction precedes neuron loss in cerebral organoids with MAPT mutations [scRNA-Seq]

Project description:Glutamatergic dysfunction precedes neuron loss in cerebral organoids with MAPT mutations [scRNA-Seq]

| PRJNA719158 | ENA

RNA sequencing data of Wild Type and Fmr1 KO hippocampal neuron

Project description:Fragile X syndrome (FXS), caused by mutations in fragile X mental retardation 1 gene (FMR1), is a prevailing genetic disorder of intellectual disability and autism. Analysis of transcriptome outcome (differentially expressed genes between WT and Fmr1 KO hippocampal neuron) associated with FXS reveal promising value of gene signature-based computation in repurposing drugs for potential practical treatment.

2019-12-05 | GSE114015 | GEO

Dual leucine zipper kinase is required for excitotoxicity induced neuronal degeneration

Project description:To investigate the role of DLK in the adult brain, we generated mice in which excision of the DLK allele can be temporally controlled to avoid the lethality observed at early postnatal ages in DLK null mice (Hirai et al., 2006). This was done by crossing mice with DLK exons 2-5 flanked by loxP sites (DLKlox/lox) to a Tamoxifen inducible Cre-ERT transgene driven by the CMV early enhancer/chicken beta actin (CAG) promoter that expresses high levels of Cre-ERT in brain and most peripheral tissues (Hayashi and McMahon, 2002). DLKlox/lox /Cre-ERTpos mice (referred to as DLKlox;Crepos) displayed minimal recombination of the DLK allele in the absence of Tamoxifen and survived to adulthood. To induce DLK recombination, 10-12 week old DLKlox;Crepos mice were put on a Tamoxifen diet for three weeks combined with three high dose injections of Tamoxifen, which resulted in efficient excision of DLK in most brain regions. Although the vast majority of DLK protein was eliminated in many brain regions one week after completion of Tamoxifen dosing, a small amount of DLK protein was still present, consistent with the levels of unrecombined DLK observed by PCR in each brain region. Nonetheless, this dosing regimen achieved a reduction in DLK levels that was adequate to assess the function of this kinase in the adult CNS and thus, avoid confounding developmental phenotypes. To examine what changes in gene expression resulted from Tamoxifen induced excision of DLK, we performed microarray analysis on the hippocampi of five Tamoxifen treated DLKlox;Crepos (conditional knock-outs, cKO) and five DLKlox;Creneg (WT) aged matched controls. Gene expression of adult hippocampus was compared betwween DLK wild-type and DLK conditional knockout mice.

2013-08-28 | E-GEOD-50245 | biostudies-arrayexpress

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