{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:30:35Z","timestamp":1790742635994,"version":"4.1.0"},"reference-count":63,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2015,10,27]],"date-time":"2015-10-27T00:00:00Z","timestamp":1445904000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2015,12,31]],"date-time":"2015-12-31T00:00:00Z","timestamp":1451520000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2015,12,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>During infections with the protozoan parasite<jats:named-content content-type=\"genus-species\">Toxoplasma gondii<\/jats:named-content>, 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<jats:italic>Toxoplasma<\/jats:italic>interferes with GABA signaling in the brain. Here, we show that while excitatory glutamatergic presynaptic proteins appeared normal, infection with type II ME49<jats:italic>Toxoplasma<\/jats:italic>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,<jats:italic>Toxoplasma<\/jats:italic>-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<jats:italic>Toxoplasma<\/jats:italic>-infected individuals are due, at least in part, to changes in GABAergic signaling.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Infections of the central nervous system can cause seizures. While inflammation in the brain has been proposed to initiate the onset of the seizures, relatively little is known about how inflammation impacts the structure and function of the neurons. Here we used a parasite called<jats:named-content content-type=\"genus-species\">Toxoplasma gondii<\/jats:named-content>that infects the brain and showed that seizures arise due to a defect in signaling of GABA, which is the neurotransmitter primarily responsible for preventing the onset of seizures.<\/jats:p>","DOI":"10.1128\/mbio.01428-15","type":"journal-article","created":{"date-parts":[[2015,10,28]],"date-time":"2015-10-28T07:19:16Z","timestamp":1446016756000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":110,"title":["Toxoplasma gondii Infections Alter GABAergic Synapses and Signaling in the Central Nervous System"],"prefix":"10.1128","volume":"6","author":[{"given":"Justin M.","family":"Brooks","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, SUNY at Buffalo School of Medicine, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela L.","family":"Carrillo","sequence":"additional","affiliation":[{"name":"Virginia Tech Carilion Research Institute, Roanoke, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianmin","family":"Su","sequence":"additional","affiliation":[{"name":"Virginia Tech Carilion Research Institute, Roanoke, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Lindsay","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Fox","sequence":"additional","affiliation":[{"name":"Virginia Tech Carilion Research Institute, Roanoke, Virginia, USA"},{"name":"Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ira J.","family":"Blader","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, SUNY at Buffalo School of Medicine, Buffalo, New York, USA"},{"name":"Department of Ophthalmology, SUNY at Buffalo School of Medicine, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2013.00195"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199801013380104"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-009-0080-z"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2007.00988.x"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2011.03.018"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2009.04.003"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.2741\/Weiss"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.12.8485"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2006.00735.x"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-02-0666"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1220272110"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01722-14"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003823"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.62.081307.162925"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2011.06.005"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.64.12.5193-5198.1996"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00085-07"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu265"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1984.03350070031018"},{"key":"e_1_3_2_21_2","doi-asserted-by":"crossref","first-page":"798","DOI":"10.4049\/jimmunol.157.2.798","article-title":"In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha","volume":"157","author":"Gazzinelli RT","year":"1996","unstructured":"Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kuhn R, Muller W, Trinchieri G, Sher A. 1996. 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