Microglial Rac1 is essential for experience-dependent brain plasticity and cognitive performance
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Microglia, the largest population of brain immune cells, continuously interact with synapses to maintain brain homeostasis. In this study, we use conditional cell-specific gene targeting in mice with multi-omics approaches and demonstrate that the RhoGTPase Rac1 is an essential requirement for microglia to sense and interpret the brain microenvironment. This is crucial for microglia-synapse crosstalk that drives experience-dependent plasticity, a fundamental brain property impaired in several neuropsychiatric disorders. Phosphoproteomics profiling detects a large modulation of RhoGTPase signaling, predominantly of Rac1, in microglia of mice exposed to an environmental enrichment protocol known to induce experience-dependent brain plasticity and cognitive performance. Ablation of microglial Rac1 affects pathways involved in microglia-synapse communication, disrupts experience-dependent synaptic remodeling, and blocks the gains in learning, memory, and sociability induced by environmental enrichment. Our results reveal microglial Rac1 as a central regulator of pathways involved in the microglia-synapse crosstalk required for experience-dependent synaptic plasticity and cognitive performance.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 113447 |
| Tidsskrift | Cell Reports |
| Vol/bind | 42 |
| Udgave nummer | 12 |
| Antal sider | 28 |
| ISSN | 2211-1247 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Work in the JBR laboratory was financed by Portuguese funds through FCT— Fundação para a Ciência e a Tecnologia/Ministério da Ciência , Tecnologia e Ensino Superior in the framework of the project PTDC/MED-NEU/1677/2021 . Work in the TS laboratory was financed by Portuguese funds through FCT— Fundação para a Cie^ncia e a Tecnologia/Ministério da Cie^ncia , Tecnologia e Ensino Superior in the framework of the project PTDC/SAU-TOX/0067/2021 and 2022.03699.CEECIND . I.M.P. acknowledges funding from European Union’s Seventh Framework Program for research, technological development and demonstration (Marie Curie Actions) under grant agreement no 600375 . C.C.P. and R.S. hold employment contracts financed by national funds through FCT —in the context of the program-contract described in paragraphs 4, 5, and 6 of art. 23 of Law no. 57/2016, of August 29, as amended by Law no. 57/2017 of July 2019. T.O.A. and J.T.M. were financed by the FSE - Fundo Social Europeu - through Norte2020 - Programa Operacional Regional Norte and by Portuguese funds through FCT - Fundação para a Ciência e Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior. FCT scholarship references: SFRH/BD/147981/2019 and UI/BD/151552/2021 . The authors acknowledge the support of the following i3S Scientific Platforms: Advanced Light Microscopy (A.L.M.), a member of the national infrastructure PPBI-Portuguese Platform of BioImaging; Animal Facility; Cell culture and Genotyping; Genomics; Proteomics; and Translational Cytometry.
Funding Information:
Work in the JBR laboratory was financed by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project PTDC/MED-NEU/1677/2021. Work in the TS laboratory was financed by Portuguese funds through FCT—Fundação para a Cie^ncia e a Tecnologia/Ministério da Cie^ncia, Tecnologia e Ensino Superior in the framework of the project PTDC/SAU-TOX/0067/2021 and 2022.03699.CEECIND. I.M.P. acknowledges funding from European Union's Seventh Framework Program for research, technological development and demonstration (Marie Curie Actions) under grant agreement no 600375. C.C.P. and R.S. hold employment contracts financed by national funds through FCT—in the context of the program-contract described in paragraphs 4, 5, and 6 of art. 23 of Law no. 57/2016, of August 29, as amended by Law no. 57/2017 of July 2019. T.O.A. and J.T.M. were financed by the FSE - Fundo Social Europeu - through Norte2020 - Programa Operacional Regional Norte and by Portuguese funds through FCT - Fundação para a Ciência e Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior. FCT scholarship references: SFRH/BD/147981/2019 and UI/BD/151552/2021. The authors acknowledge the support of the following i3S Scientific Platforms: Advanced Light Microscopy (A.L.M.), a member of the national infrastructure PPBI-Portuguese Platform of BioImaging; Animal Facility; Cell culture and Genotyping; Genomics; Proteomics; and Translational Cytometry. Conceptualization—R.S. C.C.P. A.F.A. C.B. T.S. and J.B.R.; formal analyses—R.S. T.O.A. J.G.F. B.R. I.S.M. and I.M.P.; funding acquisition—R.S. A.F.A. T.S. I.M.P. and J.B.R.; investigation—R.S. T.O.A. C.C.P. E.C.S.S. J.T.M. J.G.F. T.C. F.I.B. and A.M.; resources—A.F.A. C.B. T.S. I.M.P. and J.B.R.; supervision—R.S. and J.B.R.; validation—R.S. T.O.A. C.C.P. and J.B.R.; visualization—R.S. and T.O.A.; writing original draft—R.S. C.C.P. A.F.A. C.B. B.R. I.S.M. T.S. I.M.P. and J.B.R.; writing review and editing—R.S. T.O.A. and J.B.R. The authors declare no conflict of interest. We support inclusive, diverse, and equitable conduct of research.
Publisher Copyright:
© 2023 The Authors
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