GLT-1-Dependent Disruption of CNS Glutamate Homeostasis and Neuronal Function by the Protozoan Parasite Toxoplasma gondii

Abstract

The immune privileged nature of the CNS can make it vulnerable to chronic and latent infections. Little is known about the effects of lifelong brain infections, and thus inflammation, on the neurological health of the host. Toxoplasma gondii is a parasite that can infect any mammalian nucleated cell with average worldwide seroprevalence rates of 30%. Infection by Toxoplasma is characterized by the lifelong presence of parasitic cysts within neurons in the brain, requiring a competent immune system to prevent parasite reactivation and encephalitis. In the immunocompetent individual, Toxoplasma infection is largely asymptomatic, however many recent studies suggest a strong correlation with certain neurodegenerative and psychiatric disorders. Here, we demonstrate a significant reduction in the primary astrocytic glutamate transporter, GLT-1, following infection with Toxoplasma. Using microdialysis of the murine frontal cortex over the course of infection, a significant increase in extracellular concentrations of glutamate is observed. Consistent with glutamate dysregulation, analysis of neurons reveal changes in morphology including a reduction in dendritic spines, VGlut1 and NeuN immunoreactivity. Furthermore, behavioral testing and EEG recordings point to significant changes in neuronal output. Finally, these changes in neuronal connectivity are dependent on infection-induced downregulation of GLT-1 as treatment with the ß-lactam antibiotic ceftriaxone, rescues extracellular glutamate concentrations, neuronal pathology and function. Altogether, these data demonstrate that following an infection with T. gondii, the delicate regulation of glutamate by astrocytes is disrupted and accounts for a range of deficits observed in chronic infection.

Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents

“…With this mechanism in mind, ceftriaxone is nowadays under active consideration as a therapy in models of AD [235], stroke [236], TBI [237–239], and PD [240–243]. The most complete evidence consistent with this approach to date is a very recent extensive report on ceftriaxone rescuing brain function in Toxoplasma gondii -infected mice [244]. The authors documented high brain glutamate, although how this arose remains uncertain.…”

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

“…Toxoplasma effectively disrupts glutamate homeostasis in the infected brain [82••]. This is achieved by the selective downregulation of the primary astrocyte glutamate transporter GLT1 [82••].…”

“…This is achieved by the selective downregulation of the primary astrocyte glutamate transporter GLT1 [82••]. Astrocytes serve as a critical buffer to clear extracellular glutamate which is neurotoxic and drives changes in neuronal architecture and morphology that interfere with efficient neuronal function [83].…”

“…Astrocytes serve as a critical buffer to clear extracellular glutamate which is neurotoxic and drives changes in neuronal architecture and morphology that interfere with efficient neuronal function [83]. The Wilson group, in a recent study, functionally demonstrated using microdialysis of the murine frontal cortex that levels of free glutamate were higher in the infected brain over the course of infection [82••]. While the specific molecular mechanism and parasite are not known, the finding that neuronal dysregulation in chronic toxoplasma infections can be driven by an effect on astrocyte functions reveals that this dysregulation is as sophisticated as it is complex.…”

Acquisition, Maintenance and Relapse-Like Alcohol Drinking: Lessons from the UChB Rat Line

“…An additional link between neuroinflammation and an increased glutamatergic signal has been recently reported (David et al, 2016). The authors demonstrated a significant reduction in the primary astrocytic glutamate transporter, GLT-1 and increases in extracellular glutamate levels induced by neuroinflammation following an infection due to toxoplasma administration to mice.…”