title: Alterations in microglial phenotype and hippocampal neuronal function in transgenic mice with astrocyte-targeted production of interleukin-10.
abstract: Interleukin-10 (IL-10) is a cytokine classically linked with anti-inflammatory and protective functions in the central nervous system (CNS) in different neurodegenerative and neuroinflammatory conditions. In order to study the specific role of local CNS produced IL-10, we have created a new transgenic mouse line with astrocyte-targeted production of IL-10 (GFAP-IL10Tg). In the present study, the effects of local CNS IL-10 production on microglia, astrocytes and neuronal connectivity under basal conditions were investigated using immunohistochemistry, molecular biology techniques, electrophysiology and behavioural studies. Our results showed that, in GFAP-IL10Tg animals, microglia displayed an increase in density and a specific activated phenotype characterised by morphological changes in specific areas of the brain including the hippocampus, cortex and cerebellum that correlated with the level of transgene expressed IL-10 mRNA. Distinctively, in the hippocampus, microglial cells adopted an elongated morphology following the same direction as the dendrites of pyramidal neurons. Moreover, this IL-10-induced microglial phenotype showed increased expression of certain molecules including Iba1, CD11b, CD16/32 and F4/80 markers, "de novo" expression of CD150 and no detectable levels of either CD206 or MHCII. To evaluate whether this specific activated microglial phenotype was associated with changes in neuronal activity, the electrophysiological properties of pyramidal neurons of the hippocampus (CA3-CA1) were analysed in vivo. We found a lower excitability of the CA3-CA1 synapses and absence of long-term potentiation (LTP) in GFAP-IL10Tg mice. This study is the first description of a transgenic mouse with astrocyte-targeted production of the cytokine IL-10. The findings indicate that IL-10 induces a specific activated microglial phenotype concomitant with changes in hippocampal LTP responses. This transgenic animal will be a very useful tool to study IL-10 functions in the CNS, not only under basal conditions, but also after different experimental lesions or induced diseases.
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Institute of Neuroscience, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain. Electronic address: beatriz.almolda@uab.cat.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Almolda
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Institute of Neuroscience, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: de Labra
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Institute of Neuroscience, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Iliana
authors.initials: I
authors.lastname: Barrera
authors.affiliation: Division of Neurosciences, Pablo de Olavide University, Seville 41013, Spain.
authors.forename: Agnès
authors.initials: A
authors.lastname: Gruart
authors.affiliation: Division of Neurosciences, Pablo de Olavide University, Seville 41013, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Delgado-Garcia
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Institute of Neuroscience, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Nàdia
authors.initials: N
authors.lastname: Villacampa
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Università degli Studi di Modena e Reggio Emilia, 41125, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Vilella
authors.affiliation: School of Molecular Bioscience, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Hofer
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Institute of Neuroscience, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
authors.affiliation: School of Molecular Bioscience, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Institute of Neuroscience, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: González
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Institute of Neuroscience, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Castellano
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism*; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics*; D017774:Long-Term Potentiation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D000943:Antigens, Differentiation; D039481:CD11b Antigen; D002135:Calcium-Binding Proteins; C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; D005904:Glial Fibrillary Acidic Protein; C556062:IL10 protein, mouse; D008840:Microfilament Proteins; D012333:RNA, Messenger; D017452:Receptors, IgG; C036763:monocyte-macrophage differentiation antigen; D016753:Interleukin-10
keywords: CD11b; CD150; CD16/32; Cytokine; F4/80; GFAP; Gliosis; IL-10R; Iba1; LTP; Microglial plasticity; Neuroinflammation; Transgenic mice