Complement-dependent loss of inhibitory synapses on pyramidal neurons following Toxoplasma gondii infection

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dc.contributor.authorCarrillo, Gabriela L.en
dc.contributor.authorSu, Jianminen
dc.contributor.authorCawley, Mikel L.en
dc.contributor.authorWei, Dereken
dc.contributor.authorGill, Simran K.en
dc.contributor.authorBlader, Ira J.en
dc.contributor.authorFox, Michael A.en
dc.date.accessioned2023-03-23T15:02:06Zen
dc.date.available2023-03-23T15:02:06Zen
dc.date.issued2023-01-23en
dc.description.abstractThe apicomplexan parasite Toxoplasma gondii has developed mechanisms to establish a central nervous system infection in virtually all warm-blooded animals. Acute T. gondii infection can cause neuroinflammation, encephalitis, and seizures. Meanwhile, studies in humans, nonhuman primates, and rodents have linked chronic T. gondii infection with altered behavior and increased risk for neuropsychiatric disorders, including schizophrenia. These observations and associations raise questions about how this parasitic infection may alter neural circuits. We previously demonstrated that T. gondii infection triggers the loss of inhibitory perisomatic synapses, a type of synapse whose dysfunction or loss has been linked to neurological and neuropsychiatric disorders. We showed that phagocytic cells (including microglia and infiltrating monocytes) contribute to the loss of these inhibitory synapses. Here, we show that these phagocytic cells specifically ensheath excitatory pyramidal neurons, leading to the preferential loss of perisomatic synapses on these neurons and not those on cortical interneurons. Moreover, we show that infection induces an increased expression of the complement C3 gene, including by populations of these excitatory neurons. Infecting C3-deficient mice with T. gondii revealed that C3 is required for the loss of perisomatic inhibitory synapses. Interestingly, loss of C1q did not prevent the loss of perisomatic synapses following infection. Together, these findings provide evidence that T. gondii induces changes in excitatory pyramidal neurons that trigger the selective removal of inhibitory perisomatic synapses and provide a role for a nonclassical complement pathway in the remodeling of inhibitory circuits in the infected brain.en
dc.description.notesAcknowledgements: We thank the LaMantia and Farris labs for generously supplying some antibodies used in these experiments. A pre-print version of this manuscript was posted to bioRxiv on 08/01/2022 (). All experiments were conducted in compliance with the ARRIVE guidelines.en
dc.description.sponsorship[08/01/2022]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1111/jnc.15770en
dc.identifier.eissn1471-4159en
dc.identifier.pmid36683435en
dc.identifier.urihttp://hdl.handle.net/10919/114162en
dc.language.isoenen
dc.publisherWileyen
dc.rightsCreative Commons Attribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.subjectcomplementen
dc.subjectinhibitory synapseen
dc.subjectmicrogliaen
dc.subjectparvalbumin interneuronen
dc.subjectpyramidal neuronen
dc.subjectToxoplasma gondiien
dc.titleComplement-dependent loss of inhibitory synapses on pyramidal neurons following Toxoplasma gondii infectionen
dc.title.serialJournal of Neurochemistryen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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Scholarly Works, Fralin Biomedical Research Institute at VTC
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Scholarly Works, School of Neuroscience
Scholarly Works, Virginia Tech Carilion School of Medicine (VTCSOM)