Astroglial TNFR2 signaling regulates hippocampal synaptic function and plasticity in a sex dependent manner
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PROVIDER: PRJNA1220048 | ENA |
REPOSITORIES: ENA
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Project description:Astrocytes participate in synaptic transmission and plasticity through tightly regulated, bidirectional communication with neurons, both pre- and post-synaptic elements, as well as microglia and oligodendrocytes. A key component of astrocyte-mediated synaptic regulation is the cytokine tumor necrosis factor (TNF). TNF signals via two cognate receptors, TNFR1 and TNFR2, both expressed in astrocytes. While TNFR1 signaling in astrocytes has been long demonstrated to be necessary for physiological synaptic function, the role of astroglial TNFR2 has never been explored. Here, we demonstrate that astroglial TNFR2 is essential for maintaining hippocampal synaptic function and plasticity in physiological conditions. Indeed, GfapcreERT2:Tnfrsf1bfl/fl mice with selective ablation of TNFR2 in astrocytes exhibited dysregulated expression of neuronal and glial proteins (e.g. SNARE complex molecules, glutamate receptor subunits, glutamate transporters) essential for hippocampal synaptic transmission and plasticity. Hippocampal astrocytes sorted from GfapcreERT2:Tnfrsf1bfl/fl mice displayed downregulation of genes and pathways implicated in synaptic plasticity, astrocyte-neuron and astrocyte-oligodendrocyte communication. These alterations were accompanied by increased glial reactivity and impaired astrocyte calcium dynamics, and ultimately translated into functional deficits, specifically impaired long-term potentiation (LTP) and cognitive functions. Notably, male GfapcreERT2:Tnfrsf1bfl/fl mice exhibited more pronounced hippocampal synaptic and cellular alterations, suggesting sex-dependent differences in astroglial TNFR2 regulation of synaptic function. Together, these findings indicate that TNFR2 signaling in astrocytes is essential for proper astrocyte-neuron communication at the basis of synaptic function, and that this is regulated in a sex-dependent manner.
2025-08-01 | GSE288931 | GEO
Project description:Chronic neuropathic pain develops due to persistant neuroinflammation and maladaptive synaptic plasticity in the central nervous system following nerve injury. While TNFR2 signaling has been extensively studied in pain resolution, its expression on specific neuronal populations and the molecular pathways involved in spontaneous pain recovery remain unknown. In this, study, we investigated the role of TNFR2 within hippocampal Nex/Neurod6+ pyramidal neurons in promoting recovery from chronic constriction injury (CCI). To achieve neuron-specific deletion of TNFR2, we generated tamoxifen-inducible conditional knockout mice (NexCreERT2:TNFR2F/F). We demonstrate that TNFR2 deletion from Nex/Neurod6+ neurons prevents spontaneous pain recovery in both sexes. Exogenous administration of a TNFR2 agonist significantly improved mechanial withdrawal thresholds in both sexes of wld-type mice but did not alleviate pain in NexCreERT2:TNFR2F/F, indicating that Nex-TNFR2 expression is required for TNFR2-mediated analgesia. Bulk RNA sequencing of hippocampal (Hc) tissue collected six weeks after CCI revealed that TNFR2 activation upregulates genes Pomc and oleoyl-ACP-hydrolase (Olah). Immunostaining also showed that TNFR2 agonism restored cornu ammonis 3 (CA3) region POMC and β-Endorphin protein levels that were suppresed after CCI. A behavioral experiment demonstrated that systemic blockade of the u-opioid receptor with naltrexone prevented TNFR2-mediated pain recovery in males but only partially in females. In contrast, inhibition of cannabinoid 1 receptor (CB1R) signaling abolished TNFR2-driven analgesia in both sexes. Together, these data reveal that Hc TNFR2 signaling in Nex+ neurons is critical for CNP recovery and TNFR2 acivation promotes analgesia by engaging endogenous u-opioid and endocannabinoid pathways in a sex-dependent manner
2026-06-01 | GSE333494 | GEO
Project description:Children today experience widespread circadian disruption from nighttime screen use and irregular sleep, yet how internal clocks shape brain development is unclear. Adolescence is a critical window when synaptic connectivity is refined, in part by microglia that engulf synaptic elements. Here, in adolescent mice, we show that hippocampal microglia exhibit diurnal transcriptional rhythms, with synaptic pruning gene expression peaking during the rest phase. Inducible deletion of the core clock gene Bmal1 in microglia abolishes these rhythms and alters developing hippocampal synapses in a sex-dependent manner. In males, clock disruption increases synapse engulfment, reduces dendritic spine density, and decreases synaptic connectivity; females show similar reductions in synaptic connectivity without overt postsynaptic structural changes. Microglial clock disruption also induces broad, sex-specific changes in synapse-related gene expression that overlap with neurodevelopmental disorder pathways and lead to impaired memory and sociability, indicating microglial clocks as key regulators of developmental synapse refinement.
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2019-02-13 | GSE111384 | GEO
Project description:Synapse formation is a dynamic process essential for neuronal circuit development and maturation. At the synaptic cleft, trans-synaptic protein-protein interactions constitute major biological determinants of proper synapse efficacy. The balance of excitatory and inhibitory synaptic transmission (E-I balance) stabilizes synaptic activity and its dysregulation has been implicated in neurodevelopmental disorders including autism spectrum disorders. However, the molecular mechanisms underlying E-I balance remains to be elucidated. Here, we investigate Neuroligin (Nlgn) genes which encode a family of postsynaptic adhesion molecules that shape excitatory and inhibitory synaptic function. We identified that NLGN3 protein differentially regulates inhibitory synaptic transmission in a splice isoform-dependent manner in hippocampal CA1 synapses. Distinct subcellular localization patterns of NLGN3 isoforms contribute to the functional differences observed among splice variants. Finally, our single-cell sequencing analysis reveals that Nlgn1 and Nlgn3 are the major Nlgn genes and that Nlgn splice isoforms are highly diverse in CA1 pyramidal neurons.
2020-05-05 | GSE143295 | GEO
Project description:Synaptic scaling regulates the transcriptome in hippocampal neurons
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Project description:LC/MS/MS analysis was performed on astroglial exosome samples (3 biological replicates) to identify proteins expressed on the surface of astroglial exosomes. Thes astroglial exosome samples were purified using size-exclusion column from astrocyte conditioned medium (ACM) of primary astrocyte cultures.
2023-08-10 | PXD040650 | Pride
Project description:Here we isolate high quality synaptosomes from the hippocampus of young wild type mice and provide, at an unprecedented level, the coding and small non-coding synaptic RNAome. These data are complimented by a novel approach to analyze the synaptic RNAome from primary hippocampal neurons grown in microfluidic chambers. Our data show that synaptic microRNAs control almost the entire synaptic mRNAome and we identified several hub microRNAs. By combining the in vivo synaptosomal data with our novel microfluid chamber system, we also provide evidence to support the hypothesis that part of the synaptic microRNAome may be supplied to neurons via astrocytes. Moreover, the microfluidic system is suitable to study the dynamics of the synaptic RNAome in response to stimulation as shown with KCL treatment.
2021-02-22 | GSE159248 | GEO
Project description:PURPOSE: The goal of this study was to determine the gene expression networks regulated by tumor necrosis factor receptor 2 (TNFR2, or Tnfrsf1b) and to evaluate their potential bearing on immune cell subsets and inflammatory bowel disease (IBD). METHODS: mRNA-seq was performed on isolated distal colons from TNFR2-knockout and wildtype mice. Differentially expressed transcripts were compared to human ulcerative colitis microarray datasets on Gene Expression Omnibus and to mouse immunological expression datasets at the Immunological Genome Project. RESULTS: We identified 252 mouse transcripts whose expressions were significantly altered by the loss of TNFR2. The majority of these transcripts (228 of 252, ~90%) were downregulated in TNFR2-/- colons. TNFR2-regulated genes were able to positively discriminate between ulcerative colitis patients and healthy individuals with ~80% accuracy. Many TNFR2-regulated genes were also highly expressed in CD8+ T cells. CONCLUSIONS: Downregulation of TNFR2 is associated with a gene expression profile that is prominent in IBD and supportive of the role of CD8+ T cells in IBD pathogenesis. MANUSCRIPT ABSTRACT: Increased tumor necrosis factor (TNF) production has been associated with inflammatory bowel disease (IBD), and anti-TNF therapy is a common therapeutic for this patient population. However, the role of TNF or its receptors (TNFR1 and TNFR2) in the immunopathogenesis of inflammatory bowel disease (IBD) remains unclear. Here we report that TNFR2 is protective in spontaneous (IL-10 knockout) and chemically (azoxymethane/dextran sodium sulfate)-induced mouse models of colitis and colitis-associated cancer. Mechanistically, TNFR2-deficiency in hematopoietic cells significantly increased incidence and severity of colitis and colitis-associated cancer characterized by a selective expansion of CD8+ T cells. We identified TNFR2-regulated genes in the colon that were specific for CD8+ T cells, interacted with multiple IBD risk genes, and are important regulators of CD8+ T cell biology. TNFR2 regulated CD8+ T-cell-specific genes that act as genetic susceptibility modifiers for IBD to mitigate the development of a pro-colitogenic milieu. Antibody-mediated depletion of CD8+ T cells prevented colonic inflammation and significantly reduced pathology in IL10-/-/TNFR2-/- deficient mice. Furthermore, adoptive transfer of TNFR2-/- naïve CD8+ T cells resulted in more severe disease than with wildtype naïve CD8+ T cells. Our findings provide insight into the disease modifier role of TNFR2 in the immunopathogenesis of IBD through the modulation of CD8+ T cell responses and support future investigation of this therapeutic target, especially in the subset of IBD patients with CD8+ T-cell dysfunction. Total RNA from distal colons of 8 week-old male wildtype C57Bl/6 and TNFR2-/- mice (n=3 each) was isolated using the PureLink RNA kit (Ambion, Life Technologies). RNA samples were submitted to the Genomic Services Lab at the HudsonAlpha Institute for Biotechnology (Huntsville, AL) for multiplex library preparation, mRNA enrichment, and sequencing. Sequencing was performed to an average depth of 50M paired-end 50bp reads per sample (HiSeq, Illumina, San Diego, CA). Data files containing raw reads were aligned to the mouse genome using Tophat2/Bowtie2. Alignments were assembled into transcript representations with Cufflinks, and statistical tests for differential expression were performed with Cuffdiff 2. An adjusted P value < 0.05 (q<0.05) from the Cuffdiff 2 output was used as the cutoff for statistical significance.
2015-08-11 | E-GEOD-65408 | biostudies-arrayexpress
Project description:Neural circuits utilize a host of homeostatic plasticity mechanisms, including synaptic scaling, to maintain stability in circuits undergoing experience-dependent remodeling necessary for information processing. During synaptic scaling, compensatory adaptations in synaptic strength are induced after chronic manipulations in neuronal firing, but our understanding of this process is largely limited to its initial induction. How these homeostatic synaptic adaptations evolve when activity renormalizes and their impact on subsequent homeostatic compensation are both poorly understood. To examine these issues, we investigated whether a previous history of homeostatic scaling in networks of cultured hippocampal neurons altered their subsequent homeostatic responses to chronic activity manipulations. Unexpectedly, we found that a history of synaptic scaling strongly suppressed future scaling to the same, and even opposite, activity challenges. This history-dependent suppression was specific for future homeostatic compensation, as networks with a prior scaling history showed no deficits in the chemical induction of long-term potentiation (cLTP), a Hebbian form of synaptic plasticity. Hippocampal neurons with a prior scaling history exhibited normal engagement of activity-dependent signaling during subsequent activity challenges (as assessed by examination of the ERK/MAPK pathway) but demonstrated widespread alterations in activity-dependent transcriptional
2024-09-01 | GSE180993 | GEO