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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE244773 | GEO | 2023/10/23

REPOSITORIES: GEO

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

Project description: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.

2023-10-23 | PXD045719 | Pride

Effect of Rac1 haploinsufficiency on the gene expression profile of mouse endothelial cells

Project description:The therapeutic potential of neurotrophic factors has been hampered by their inability to achieve adequate tissue penetration. Brain blood vessels, however, could be an alternative target for neuro-salvage therapies by virtue of their close proximity to neurons. Here we show that hemizygous deletion of Rac1 in mouse endothelial cells (ECs) attenuates brain injury and edema following focal cerebral ischemia. To explore the mechanisms whereby decrease of Rac1 in ECs provide neuroprotection, ECs were derived from Rac1+/+ and Rac1+/- mice. Microarray analysis was performed to determine the differential gene expression between Rac1+/+ and Rac1+/- ECs. Rac1+/+ and Rac1+/- ECs were cultured to subconfluence. Total RNA was extracted and reverse transcribed. Rac1+/+ (n = 2) and Rac1+/- (n = 2) EC cDNAs were labeled with Cy3 and Cy5, respectively, and equimolar mixtures of labeled Rac1+/+ and Rac1+/- probes were hybridized to 2 slides (sample #21648, #21649). Additionally, Rac1+/+ (n = 2) and Rac1+/- (n=2) EC cDNAs labeled with Cy5 and Cy3 (dye-swapping) were hybridized to 2 slides (sample #21650, #21651). Comparison of signal intensities between Rac1+/+ (channel 2) and Rac1+/- (channel 1) was conducted on each slide (sample), and the ratio of intensities from 4 slides were statistically assessed for each gene feature to investigate differential gene expression.

2009-03-15 | E-GEOD-15003 | biostudies-arrayexpress

Effect of Rac1 haploinsufficiency on the gene expression profile of mouse endothelial cells

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Transcriptome of K14 V12 Rac1 mice

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Project description:Interactors of double mutant Rac1 (P29S/Q61L) compared to constitutively active Rac1 (Q61L).

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Transcription profiling of rac1 knock-down zebrafish embryos

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GABA-receptive microglia selectively sculpt developing inhibitory circuits

Project description:Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and therefore wiring precision. However, whether the remodeling of distinct synapses during development is mediated by specialized microglia is unknown. Here, using in vivo two-photon imaging, we show that GABA-receptive microglia selectively interact with inhibitory synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABAB receptors within microglia impairs this process and leads to stereotyped repetitive behavior and hyperactivity. These findings demonstrate that distinct microglia differentially engage with specific synapse types during development.

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Rescuing over-activated microglia by acetaminophen treatment restores cognitive performance in the Dp(16) mouse model of Down Syndrome.

Project description:Microglia are the resident immune cells of the brain and have been implicated in mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by the presence of a supernumerary chromosome 21, which contains genes essential for the function of the immune system. Here, we investigated the presence of microglial alterations and their implication for cognitive impairment in the Dp(16) mouse model of DS. In the hippocampus of Dp(16) mice and individuals with DS, we found microglial morphology indicative of an activated state. Accordingly, we found increased levels of pro-inflammatory cytokines and altered interferon signaling in Dp(16) mice. In addition, Dp(16) mice showed decreased dendritic spine density and cognitive deficits. Remarkably, depletion of defective microglia by PLX3397 treatment or rescue of the microglia activated state by the commonly used anti-inflammatory drug acetaminophen fully rescued dendritic-spine density and cognitive deficits in Dp(16) mice. Our data suggest an involvement of microglia in the cognitive impairment of DS animals and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.

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Rescuing over-activated microglia by acetaminophen treatment restores cognitive performance in the Dp(16) mouse model of Down Syndrome.

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Meiotic crossover landscape within RAC1 disease resistance gene

Project description:To study recombination at the fine-scale, we used high-throughput sequencing of 300 to 1,000 crossovers within the RAC1 R gene hotspot. This revealed focused intragenic crossovers, overlapping exons encoding the TIR, NBS and LRR domains. To examine the role of recombination pathways, we repeated this experiment in recq4a recq4b, fancm and recq4a recq4b fancm mutants. Finally, in order to investigate how varying patterns of interhomolog divergence influence local patterns of crossover frequency, we repeated RAC1 pollen typing sequencing in different F1 hybrids.

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