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Activated Microglia-Induced Deficits in Excitatory Synapses Through IL-1β: Implications for Cognitive Impairment in Sepsis

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Abstract

Recent clinical studies have shown that sepsis survivors may develop long-term cognitive impairments. The cellular and molecular mechanisms involved in these events are not well understood. This study investigated synaptic deficits in sepsis and the involvement of glial cells in this process. Septic animals showed memory impairment and reduced numbers of hippocampal and cortical excitatory synapses, identified by synaptophysin/PSD-95 co-localization, 9 days after disease onset. The behavioral deficits and synaptophysin/PSD-95 co-localization were rescued to normal levels within 30 days post-sepsis. Septic mice presented activation of microglia and reactive astrogliosis, which are hallmarks of brain injury and could be involved in the associated synaptic deficits. We treated neuronal cultures with conditioned medium derived from cultured astrocytes (ACM) and microglia (MCM) that were either non-stimulated or stimulated with lipopolysaccharide (LPS) to investigate the molecular mechanisms underlying synaptic deficits in sepsis. ACM and MCM increased the number of synapses between cortical neurons in vitro, and these effects were antagonized by LPS stimulation. LPS-MCM reduced the number of synapses by 50 %, but LPS-ACM increased the number of synapses by 500 %. Analysis of the composition of these conditioned media revealed increased levels of IL-1β in LPS-MCM. Furthermore, inhibition of IL-1β signaling through the addition of a soluble IL-1β receptor antagonist (IL-1 Ra) fully prevented the synaptic deficit induced by LPS-MCM. These results suggest that sepsis induces a transient synaptic deficit associated with memory impairments mediated by IL-1β secreted by activated microglia.

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Acknowledgments

We thank Marcelo Meloni for technical assistance. This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Institute of Glia (iGLIA/CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). The authors declare no conflicts of interest.

Author contributions

C.A.M., G.S., T.C.L.S.S., J.D’, F.R.S.L., C.F.B., F.A.B..., and F.C.A.G. designed the research; C.A.M., G.S., T.C.L.S.S., and J.D. performed the research; C.A.M., T.C.L.S.S., J.D., F.R.S.L., C.F.B., F.A.B..., and F.C.A.G. analyzed the data; and C.A.M., F.A.B..., and F.C.A.G. wrote the manuscript.

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Authors and Affiliations

  1. Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil

    Carolina A. Moraes, Gabriel Santos, Tania Cristina Leite de Sampaio e Spohr, Flávia Regina Souza Lima, Claudia Farias Benjamim & Flávia Carvalho Alcantara Gomes

  2. Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ, Brazil

    Carolina A. Moraes, Joana C. D’Avila & Fernando A. Bozza

  3. Instituto D’Or Ensino e Pesquisa, Rio de Janeiro, Brazil

    Fernando A. Bozza

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  1. Carolina A. Moraes
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Correspondence to Flávia Carvalho Alcantara Gomes.

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Supplemental Fig. 1

ELISA of synaptic proteins in the hippocampus and cerebral cortex at 3, 9, and 30 days after CLP induction. Sepsis did not alter the levels of synaptophysin and PSD-95 in hippocampus (a, b). Only at 3 days post sepsis, a decrease of synaptophysin in the cerebral cortex was observed, while PSD-95 level remained the same between sham and CLP mice in all the days analyzed (c, d). Data are the mean ± SEM. n = 3. Student’s t test, p < 0.05 (EPS 181 kb)

Supplemental Fig. 2

LPS induces reactive gliosis and microglial activation in cultured cells. Cultures of cerebral cortex astrocytes and microglia were incubated for 24 h with DMEM-F12 (control) or 50 ng/mL and 1 μg/mL LPS. Subsequently, cultures were analyzed by immunolabeling for GFAP and F4/80, which are astrocyte and microglial markers, respectively. LPS at 50 ng/mL and 1 μg/mL increased GFAP labeling in astrocyte cultures by 91 % and 176 %, respectively (d). LPS elicited an increase of 176–220 % in the number of F4/80-positive amoeboid microglial cells (h). e’ and g’ show magnification of the squares in e and g, respectively. Data are the mean ± SEM. n = 4. ANOVA, Tukey’s post hoc test, p < 0.05. Scale bar, 10 μm (a) (GIF 25 kb)

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Moraes, C.A., Santos, G., Spohr, T.C.L.S. et al. Activated Microglia-Induced Deficits in Excitatory Synapses Through IL-1β: Implications for Cognitive Impairment in Sepsis. Mol Neurobiol 52, 653–663 (2015). https://doi.org/10.1007/s12035-014-8868-5

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