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Nature DOI:10.1038/nature18283

A complement-microglial axis drives synapse loss during virus-induced memory impairment.

Publication TypeJournal Article
Year of Publication2016
AuthorsVasek, MJ, Garber, C, Dorsey, D, Durrant, DM, Bollman, B, Soung, A, Yu, J, Perez-Torres, C, Frouin, A, Wilton, DK, Funk, K, DeMasters, BK, Jiang, X, Bowen, JR, Mennerick, S, Robinson, JK, Garbow, JR, Tyler, KL, Suthar, MS, Schmidt, RE, Stevens, B, Klein, RS
JournalNature
Volume534
Issue7608
Pages538-43
Date Published2016 06 23
ISSN1476-4687
KeywordsAnimals, CA3 Region, Hippocampal, Complement Activation, Complement Pathway, Classical, Complement System Proteins, Disease Models, Animal, Female, Humans, Male, Memory Disorders, Mice, Microglia, Neuronal Plasticity, Neurons, Presynaptic Terminals, Spatial Memory, West Nile Fever, West Nile virus
Abstract

Over 50% of patients who survive neuroinvasive infection with West Nile virus (WNV) exhibit chronic cognitive sequelae. Although thousands of cases of WNV-mediated memory dysfunction accrue annually, the mechanisms responsible for these impairments are unknown. The classical complement cascade, a key component of innate immune pathogen defence, mediates synaptic pruning by microglia during early postnatal development. Here we show that viral infection of adult hippocampal neurons induces complement-mediated elimination of presynaptic terminals in a murine WNV neuroinvasive disease model. Inoculation of WNV-NS5-E218A, a WNV with a mutant NS5(E218A) protein leads to survival rates and cognitive dysfunction that mirror human WNV neuroinvasive disease. WNV-NS5-E218A-recovered mice (recovery defined as survival after acute infection) display impaired spatial learning and persistence of phagocytic microglia without loss of hippocampal neurons or volume. Hippocampi from WNV-NS5-E218A-recovered mice with poor spatial learning show increased expression of genes that drive synaptic remodelling by microglia via complement. C1QA was upregulated and localized to microglia, infected neurons and presynaptic terminals during WNV neuroinvasive disease. Murine and human WNV neuroinvasive disease post-mortem samples exhibit loss of hippocampal CA3 presynaptic terminals, and murine studies revealed microglial engulfment of presynaptic terminals during acute infection and after recovery. Mice with fewer microglia (Il34(-/-) mice with a deficiency in IL-34 production) or deficiency in complement C3 or C3a receptor were protected from WNV-induced synaptic terminal loss. Our study provides a new murine model of WNV-induced spatial memory impairment, and identifies a potential mechanism underlying neurocognitive impairment in patients recovering from WNV neuroinvasive disease.

DOI10.1038/nature18283
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/27337340?dopt=Abstract

Alternate JournalNature
PubMed ID27337340
PubMed Central IDPMC5452615
Grant ListU19 AI083019 / AI / NIAID NIH HHS / United States
P30 CA091842 / CA / NCI NIH HHS / United States
F31 NS077640 / NS / NINDS NIH HHS / United States
T32 AI052066 / AI / NIAID NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
R01 AI101400 / AI / NIAID NIH HHS / United States
R01 NS052632 / NS / NINDS NIH HHS / United States
F30 AA023685 / AA / NIAAA NIH HHS / United States