Toxoplasma infection induces microglia‐neuron contact and the loss of perisomatic inhibitory synapses

Abstract

Infection and inflammation within the brain induces changes in neuronal connectivity and function. The intracellular protozoan parasite, Toxoplasma gondii, is one pathogen that infects the brain and can cause encephalitis and seizures. Persistent infection by this parasite is also associated with behavioral alterations and an increased risk for developing psychiatric illness, including schizophrenia. Current evidence from studies in humans and mouse models suggest that both seizures and schizophrenia result from a loss or dysfunction of inhibitory synapses. In line with this, we recently reported that persistent Toxoplasma gondii infection alters the distribution of glutamic acid decarboxylase 67 (GAD67), an enzyme that catalyzes GABA synthesis in inhibitory synapses. These changes could reflect a redistribution of presynaptic machinery in inhibitory neurons or a loss of inhibitory nerve terminals. To directly assess the latter possibility, we employed serial block face scanning electron microscopy (SBFSEM) and quantified inhibitory perisomatic synapses in neocortex and hippocampus following parasitic infection. Not only did persistent infection lead to a significant loss of perisomatic synapses, it induced the ensheathment

Microglial Displacement of GABAergic Synapses Is a Protective Event during Complex Febrile Seizures

“…During development, microglial prune numerous extra excitatory presynaptic terminals to sculpt postnatal neural circuits (Mosser et al, 2017;Schafer et al, 2012;Zhan et al, 2014). Apart from synapse pruning, microglia also displace presynapses surrounding neuronal soma under experimental conditions that mimic neuroinflammation or a transection of the mouse facial nerve (Blinzinger and Kreutzberg, 1968;Carrillo et al, 2020;Chen et al, 2014;Trapp et al, 2007); however, knowledge of the presence and contribution of such actions of microglia on neurological disorders is still lacking.…”

Injection with Toxoplasma gondii protein affects neuron health and survival

“…Given that prior work suggested that Toxoplasma infection might specifically affect inhibitory neurons ( Brooks et al, 2015 ), we first examined how often TINs co-localized with two common markers for inhibitory interneurons, calbindin and parvalbumin. We chose these makers rather than the pan-inhibitory marker glutamate decarboxylase (GAD) [GAD + interneurons make up approximately 15–20% of all cortical neurons ( Gentet et al, 2000 ; Lodato and Arlotta, 2015 )] as GAD staining is altered in Toxoplasma- infected brain ( Brooks et al, 2015 ; Carrillo et al, 2020 ). Fortunately, parvalbumin labels 40–50% of GAD + interneurons and calbindin labels approximately 30% of GAD + interneurons ( Hof et al, 1999 ; Keller et al, 2019 ).…”

Comparative Review of Microglia and Monocytes in CNS Phagocytosis

“…In the disease conditions, CX3CR1 is downregulated in microglia [37]. [39,43] Immunohistochemistry [44] CCR2 Flow cytometry…”

“…Synaptic phagocytosis has also been observed after Toxoplasma infections. Carrillo et al showed that hippocampal microglia and infiltrating monocytes in a mouse model of Toxoplasma infection stripped and phagocytosed inhibitory presynaptic terminals around the cell body [44]. Using CX3CR1-GFP mice, in which both microglia and circulating monocytes express GFP, the authors found that there was a mixture of cells with high and low GFP fluorescence intensity in the brain parenchyma.…”