<named-content content-type="genus-species">Toxoplasma gondii</named-content> Infections Alter GABAergic Synapses and Signaling in the Central Nervous System

ABSTRACT During 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...

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Autores principales:	Justin M. Brooks, Gabriela L. Carrillo, Jianmin Su, David S. Lindsay, Michael A. Fox, Ira J. Blader
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d5badc021d0040e483c82c8ecb647710
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spelling	oai:doaj.org-article:d5badc021d0040e483c82c8ecb6477102021-11-15T15:41:23Z<named-content content-type="genus-species">Toxoplasma gondii</named-content> Infections Alter GABAergic Synapses and Signaling in the Central Nervous System10.1128/mBio.01428-152150-7511https://doaj.org/article/d5badc021d0040e483c82c8ecb6477102015-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01428-15https://doaj.org/toc/2150-7511ABSTRACT During 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. IMPORTANCE 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 Toxoplasma gondii 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.Justin M. BrooksGabriela L. CarrilloJianmin SuDavid S. LindsayMichael A. FoxIra J. BladerAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 6 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Justin M. Brooks Gabriela L. Carrillo Jianmin Su David S. Lindsay Michael A. Fox Ira J. Blader <named-content content-type="genus-species">Toxoplasma gondii</named-content> Infections Alter GABAergic Synapses and Signaling in the Central Nervous System
description	ABSTRACT During 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. IMPORTANCE 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 Toxoplasma gondii 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.
format	article
author	Justin M. Brooks Gabriela L. Carrillo Jianmin Su David S. Lindsay Michael A. Fox Ira J. Blader
author_facet	Justin M. Brooks Gabriela L. Carrillo Jianmin Su David S. Lindsay Michael A. Fox Ira J. Blader
author_sort	Justin M. Brooks
title	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Infections Alter GABAergic Synapses and Signaling in the Central Nervous System
title_short	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Infections Alter GABAergic Synapses and Signaling in the Central Nervous System
title_full	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Infections Alter GABAergic Synapses and Signaling in the Central Nervous System
title_fullStr	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Infections Alter GABAergic Synapses and Signaling in the Central Nervous System
title_full_unstemmed	<named-content content-type="genus-species">Toxoplasma gondii</named-content> Infections Alter GABAergic Synapses and Signaling in the Central Nervous System
title_sort	<named-content content-type="genus-species">toxoplasma gondii</named-content> infections alter gabaergic synapses and signaling in the central nervous system
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/d5badc021d0040e483c82c8ecb647710
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<named-content content-type="genus-species">Toxoplasma gondii</named-content> Infections Alter GABAergic Synapses and Signaling in the Central Nervous System

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