Toxoplasma gondii Infections Alter GABAergic Synapses and Signaling in the Central Nervous System

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dc.contributor.authorBrooks, Justin M.en
dc.contributor.authorCarrillo, Gabriela Lizanaen
dc.contributor.authorSu, Jianminen
dc.contributor.authorLindsay, David S.en
dc.contributor.authorFox, Michael A.en
dc.contributor.authorBlader, Ira J.en
dc.date.accessioned2018-11-19T18:32:08Zen
dc.date.available2018-11-19T18:32:08Zen
dc.date.issued2015-10-27en
dc.description.abstractDuring infections with the protozoan parasite Toxoplasma gondii, gamma-aminobutyric acid (GABA) is utilized as a carbon source for parasite metabolism and also to facilitate parasite dissemination by stimulating dendritic-cell motility. The best-recognized function for GABA, however, is its role in the nervous system as an inhibitory neurotransmitter that regulates the flow and timing of excitatory neurotransmission. When this pathway is altered, seizures develop. Human toxoplasmosis patients suffer from seizures, suggesting that Toxoplasma interferes with GABA signaling in the brain. Here, we show that while excitatory glutamatergic presynaptic proteins appeared normal, infection with type II ME49 Toxoplasma tissue cysts led to global changes in the distribution of glutamic acid decarboxylase 67 (GAD67), a key enzyme that catalyzes GABA synthesis in the brain. Alterations in GAD67 staining were not due to decreased expression but rather to a change from GAD67 clustering at presynaptic termini to a more diffuse localization throughout the neuropil. Consistent with a loss of GAD67 from the synaptic terminals, Toxoplasma-infected mice develop spontaneous seizures and are more susceptible to drugs that induce seizures by antagonizing GABA receptors. Interestingly, GABAergic protein mislocalization and the response to seizure-inducing drugs were observed in mice infected with type II ME49 but not type III CEP strain parasites, indicating a role for a polymorphic parasite factor(s) in regulating GABAergic synapses. Taken together, these data support a model in which seizures and other neurological complications seen in Toxoplasma-infected individuals are due, at least in part, to changes in GABAergic signaling.en
dc.identifier.doihttps://doi.org/10.1128/mbio.01428-15en
dc.identifier.issue6en
dc.identifier.urihttp://hdl.handle.net/10919/85893en
dc.identifier.volume6en
dc.language.isoen_USen
dc.publisherAmerican Society for Microbiologyen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleToxoplasma gondii Infections Alter GABAergic Synapses and Signaling in the Central Nervous Systemen
dc.title.serialmBioen
dc.typeArticle - Refereeden
dc.type.dcmitypetexten

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