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Microglial Rac1 is essential for experience-dependent brain plasticity and cognitive performance

ABSTRACT: Here, we used conditional cell-specific gene targeting in mice with multi-omics approaches, and demonstrated that the RhoGTPase Rac1 was an essential requirement for the microglia to sense and interpret the brain microenvironment, and for crucial microglia-synapse crosstalk driving experience-dependent plasticity. Phosphoproteomics profiling detected a large modulation of RhoGTPase signaling, predominantly of Rac1, in microglia of mice exposed to an environmental enrichment protocol. Ablation of microglial Rac1 affected pathways involved in microglia-synapse communication, disrupted experience-dependent synaptic remodeling, and blocked the gains in learning, memory and sociability induced by environmental enrichment.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Tiago Almeida

LAB HEAD: João Bettencourt Relvas

PROVIDER: PXD045719 | Pride | 2023-10-23

REPOSITORIES: Pride

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Microglial Rac1 is essential for experience-dependent brain plasticity and cognitive performance

Project description:Microglia, the largest population of brain immune cells, continuously interact with synapses to maintain brain homeostasis. We aimed at understanding the role of Rac1 on microglia functions. Here, we used conditional cell-specific gene targeting in mice with multi-omics approaches, and demonstrated that the RhoGTPase Rac1 was an essential requirement for the microglia to sense and interpret the brain microenvironment, and for crucial microglia-synapse crosstalk driving experience-dependent plasticity, a fundamental brain property impaired in several neuropsychiatric disorders.

2023-10-23 | GSE244773 | GEO

Microglial remodeling of the extracellular matrix promotes synapse plasticity [Neuronal nuclei]

Project description:This study defines a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling in the hippocampus.

2020-07-01 | GSE150713 | GEO

Microglial remodeling of the extracellular matrix promotes synapse plasticity [Microglia]

Project description:This study defines a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling in the hippocampus.

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Microglia RNA-seq of mus musculus:adult male dorsal hippocampus

Project description:Engrams are considered to be substrates for memory storage, and the functional dysregulation of the engrams leads to cognition impairment.However, the cellular basis for these maladaptive changes lead to the forgetting of memories remains unclear. Here we found that the expression of autophagy protein 7 (Atg7) mRNA was dramatically upregulated in aged DG engrams, and led to the forgetting of contextual fear memory and the activation of surrounding microglia.To determine mechanism by which autophagy in DG engrams activates the surrounding microglia, mice were co-injected AAV-RAM-Cre either with AAV-Dio-Atg7-Flag or AAV-Dio- EYFP in dorsal dentate gyrus to overexpress ATG7 in the DG memory engrams. Microglia were separated using magnetic-activated cell sorting and subjected to RNA-Seq in dorsal hippocampus .Bioinformatics analysis shown overexpression of Atg7 in dorsal DG memory engrams caused an increase in the expression of Tlr2 in the surrounding microglia.Depletion of Toll-like receptor 2/4 (TLR2/4) in DG microglia prohibited excessive microglial activation and synapse elimination induced by the overexpression of ATG7 in DG engrams, and thus prevented forgetting. Furthermore, the expression of Rac1, a Rho-GTPases which regulates active forgetting in both fly and mice, was upregulated in aged engrams. Optogentic activation of Rac1 in DG engrams promoted the autophagy of the engrams, the activation of microglia, and the forgetting of fear memory. Invention of the Atg7 expression and microglia activation attenuated forgetting induced by activation of Rac1 in DG engrams. Together, our findings revealed autophagy-dependent synapse elimination of DG engrams by microglia as a novel forgetting mechanism.

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Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system

Project description:INPP5D, which encodes the lipid phosphatase SHIP1, is one of the most common genes associated with the risk of Alzheimer’s disease and is enriched in microglia in the central nervous system. SHIP1 has been found to be highly expressed in plaque-associated microglia. However, how it regulates microglial function and influences brain physiology has been poorly investigated. Here we show that SHIP1 is not only enriched in microglia associated with amyloid beta plaques, but also in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that conditional knockout mice lacking microglial SHIP1 (cKO) display increased complement and synapse loss in the early postnatal brain. Additionally, SHIP1 KO microglia show reduced morphological complexity, altered transcriptional signatures, and abnormal synaptic pruning, which is dependent on the complement system. Single nucleus RNA-sequencing analysis of the entire hippocampus confirmed decreased interaction for synaptic structure-related pathways in both excitatory and inhibitory neurons. Importantly, cKO mice show cognitive defects in adulthood only when microglial SHIP1 is depleted at early postnatal days, but not when depleted at later stages. Finally, using CRISPR/Cas9 we generated human iPSC-derived microglia lacking SHIP1, and validated the increased engulfment of synaptic structures. Altogether, these findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling through the complement system in the early postnatal brain. Disrupting this process has lasting behavioral effects and may provide a link to vulnerability to neurodegeneration.

2024-12-04 | PXD052118 | Pride

Proteomics analysis of gastric cancer patients with diabetes mellitus

Project description:Proteomics is a powerful approach to study the molecular mechanisms of cancer. In this study, we aim to characterize the proteomic profile of gastric cancer (GC) in patients with diabetes mellitus (DM) type 2. Forty GC tissue samples including 19 cases from diabetic patients and 21 cases from individuals without diabetes (control group) were selected for the proteomics analysis. Gastric tissues were processed following the single-pot, solid-phase-enhanced sample preparation approach—SP3 and enzymatic digestion with trypsin. The resulting peptides were analyzed by LC-MS Liquid Chromatography—Mass Spectrometry (LC-MS). The comparison of protein expression levels between GC samples from diabetic and non-diabetic patients was performed by label-free quantification (LFQ). A total of 6599 protein groups were identified in the 40 samples. Thirty-seven proteins were differentially expressed among the two groups, with 16 upregulated and 21 downregulated in the diabetic cohort. Statistical overresentation tests were considered for different annotation sets including the Gene Ontology(GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Disease functional databases. Upregulated proteins in the GC samples from diabetic patients were particularly enriched in respiratory electron transport and alcohol metabolic biological processes, while downregulated proteins were associated with epithelial cancers, intestinal diseases, and cell–cell junction cellular components. Taken together, these results support the data already obtained by previous studies that associate diabetes with metabolic disorders and diabetes-associated diseases, such as Alzheimer’s and Parkinson’s, and also provide valuable insights into seven GC-associated protein targets, claudin-3, polymeric immunoglobulin receptor protein, cadherin-17, villin-1, transglutaminase-2, desmoglein-2, and mucin-13, which warrant further investigation.

2021-01-22 | PXD022915 | Pride

RNA Sequencing Facilitates Quantitative Analysis of Wild Type(MRL-mpj) and MRL-lpr (PBS or MSC treated) Hippocampoal Transcriptomes

Project description:Up to 75% of systematic lupus erythematosus (SLE) patients experience neuropsychiatric (NP) symptoms, called neuropsychiatric SLE (NPSLE), yet the underlying mechanisms remain elusive. Complement cascades mediate synaptic pruning by microglia during early postnatal brain development. The process in NPSLE remains unclear. Here, we show that complement-coordinated elimination of synaptic terminals participated in NPSLE in MRL/lpr mice, a lupus-prone murine model. We elucidated that lupus mice developed increased anxiety-like behaviors and persistent phagocytic microglia reactivation before overt peripheral lupus pathology. Microglial engulfment of synapses explained behavioral disorders. We further determined that neuronal Nr4a1 signaling was essential for attracting C1q synaptic deposition then apposition of phagocytic microglia, ensuing synaptic loss and neurological disease. Minocycline-deactivated microglia, antibody-blocked C1q, or neuronal Nr4a1 restore protected lupus mice from synapse loss and NP manifestations. Our findings revealed an active role of neurons in coordinating microglia-mediated synaptic loss and highlight neuronal Nr4a1 and C1q as critical components amenable to pharmacological intervention.

2022-02-23 | GSE154288 | GEO

Single-cell sequencing of FACS-sorted mouse astrocytes, investigating the effect of absence of microglia in a mouse model of ß-amyloidopathy

Project description:The APPSwe/PS1dE9 (APP/PS1) mouse ß-amyloidopathy mouse model exhibits extracellular Aß deposition, particularly in the neocortex and hippocampus, increasing steadily from about 6 months, with reactive astrogliosis and synapse loss occurring proximal to plaques. We crossed APP/PS1 mice onto genetically modified mice which lack microglia (Csf1r ∆FIRE/∆FIRE) to assess whether Aß plaque deposition and downstream events are altered in brains lacking microglia.

2024-10-15 | E-MTAB-14233 | biostudies-arrayexpress

RNA-seq of mouse brain tissue investigating the effect of absence of microglia in a mouse model of ß-amyloidopathy

Project description:The APPSwe/PS1dE9 (APP/PS1) ß-amyloidopathy mouse model exhibits extracellular Aß deposition increasing steadily from about 6 months, particularly in the neocortex and hippocampus, with reactive astrogliosis and synapse loss occurring proximal to plaques. We crossed APP/PS1 mice onto genetically modified mice which lack microglia (Csf1r ∆FIRE/∆FIRE) to assess whether Aß plaque deposition and downstream events are altered in brains lacking microglia.

2024-10-15 | E-MTAB-14231 | biostudies-arrayexpress

Influence of a high dietary level of the microalgae Chlorella vulgaris alone and combined with exogenous carbohydrases on muscle transcriptome and proteome of finishing pigs: an integrated approach

Project description:Background: monogastric feeding is dependent on conventional feedstuffs such as corn and soybean meal. However, these are increasingly expensive and environmentally unsustainable. Therefore, there is an increasing interest in high quality and sustainable alternative feedstuffs, namely microalgae. Chlorella vulgaris is one of such alternatives, with a high level of crude protein and bioactive compounds. However, its recalcitrant cell wall hinders the digestive process. CAZyme supplementation is a possible solution to overcome such a problem. The objective of this work was to evaluate the effect of a 5% dietary C. vulgaris (CV) and enzymatic supplementation (CV+R – Rovabio® Excel AP; CV+M – four CAZyme mix) on muscle transcriptome and proteome of finishing pigs in an integrated approach. Results: there were no differences concerning the live pig production performance. Pigs that were fed with the microalga had increased deposition of n-3 PUFA, including C20:5n-3 (EPA) in the muscle. Control pigs increased the abundance of contractile apparatus (e.g. MYH1, MYH2, MYH4) and energy metabolism (e.g. CKMT1, NDUFS3) proteins, demonstrating increased nutrient availability. Moreover, they had increased abundance of SCD, characteristic of increased glucose availability via the activation of SREBP-1c and ChREBP. CV and CV+R pigs upregulated proteolytic and apoptotic genes (e.g. BAX, DDA1), whilst increasing the abundance of glucose (UQCRFS1) and fatty acid catabolism (ACADS) proteins. CV+R pigs upregulated ACOT8 and SIRT3 genes as a response to reduced nutrient availability, to maintain energy homeostasis and oxidative status. The CV+M pigs showed the least number of significant differences in both omics platforms. Conclusions: the four-CAZyme mix designed to degrade the microalgal cell wall was efficient in re-establishing the muscle metabolism, mitigating the otherwise negative effects of microalga incorporation in the diet.

2023-03-11 | PXD033814 | Pride

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