Toxoplasma gondii 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 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.

Anti-NMDA receptor autoantibodies and associated neurobehavioral pathology in mice are dependent on age of first exposure to Toxoplasma gondii

“…We see a different effect after behavior testing, which could be due to long-term effects of the psychostimulants used during testing (Li et al, 2015; Thomases et al, 2013). Our data differs from previous studies on T. gondii- infected rodents that revealed no changes in vGLUT1 and a decrease in PSD95 in the cortex (Parlog et al, 2014; Brooks et al, 2015), likely due to differences in the parasite strain, rodent strain, and rodent sex used. In addition, such differences may partly explain phenotypic differences in a lack of seizures observed in our model compared with others (Brooks et al, 2015).…”

Reexamining Chronic Toxoplasma gondii Infection: Surprising Activity for a “Dormant” Parasite

“…GABA is a metabolite used by the parasite and is also an inhibitory neurotransmitter important in epilepsy. The Blader laboratory showed that, in the course of T. gondii infection, the redistribution (but not change in levels of) of synaptic glutamic acid decarboxylase 67 (GAD67) is associated with the development of seizures [81•]. Notably, the duration and severity of seizures triggered by GABA agonists were dependent on the infecting parasite strain arguing against a generalized effect caused by infection or inflammation [81•].…”

Neurophysiological Changes Induced by Chronic <em>Toxoplasma gondii</em> Infection

“…Glutamate signalling is regulated by γ-aminobutyric acid (GABA), an inhibitory neurotransmitter which may also play an important role during infection. In infected animals the GABAergic pathway remained intact, although, global changes in localization of GAD67, the enzyme responsible for converting glutamate to GABA, were observed [83]. Interestingly, although only a small number of tissue cysts were found in infected mice, GAD67 location was disturbed throughout the brain.…”