Chronic Toxoplasma infection is associated with distinct alterations in the synaptic protein composition

Daniel Lang,Karl Heinz Smalla,Marco Van Ham,Björn H Schott,Ildiko Rita Dunay,Leonora Kulikovskaja,Lorena Morton,Rainer Pielot,Lothar Jänsch,Dirk Montag,Eckart D Gundelfinger,Rodrigo Herrera-Molina,Frank Klawonn

doi:10.1186/s12974-018-1242-1

Abstract

BackgroundChronic infection with the neurotropic parasite Toxoplasma gondii has been implicated in the risk for several neuropsychiatric disorders. The mechanisms, by which the parasite may alter neural function and behavior of the host, are not yet understood completely.MethodsHere, a novel proteomic approach using mass spectrometry was employed to investigate the alterations in synaptic protein composition in a murine model of chronic toxoplasmosis. In a candidate-based strategy, immunoblot analysis and immunohistochemistry were applied to investigate the expression levels of key synaptic proteins in glutamatergic signaling.ResultsA comparison of the synaptosomal protein composition revealed distinct changes upon infection, with multiple proteins such as EAAT2, Shank3, AMPA receptor, and NMDA receptor subunits being downregulated, whereas inflammation-related proteins showed an upregulation. Treatment with the antiparasitic agent sulfadiazine strongly reduced tachyzoite levels and diminished neuroinflammatory mediators. However, in both conditions, a significant number of latent cysts persisted in the brain. Conversely, infection-related alterations of key synaptic protein levels could be partly reversed by the treatment.ConclusionThese results provide evidence for profound changes especially in synaptic protein composition in T. gondii-infected mice with a downregulation of pivotal components of glutamatergic neurotransmission. Our results suggest that the detected synaptic alterations are a consequence of the distinct neuroinflammatory milieu caused by the neurotropic parasite.

Highlights

Chronic infection with the neurotropic parasite Toxoplasma gondii has been implicated in the risk for several neuropsychiatric disorders
Proteomics Infection-related alterations of protein composition in synaptosomes Synaptic differences between T. gondii infected and non-infected brains were analyzed at the level of synaptosomal protein abundances
Database searches were restricted to high-quality MS data and identified a total of 3062 proteins in synaptosomes from infected and non-infected mice (Additional file 3)

Summary

Introduction

Chronic infection with the neurotropic parasite Toxoplasma gondii has been implicated in the risk for several neuropsychiatric disorders. The mechanisms, by which the parasite may alter neural function and behavior of the host, are not yet understood completely. A remarkable feature of T. gondii is the parasite’s ability to alter the host’s behavior. Most studies on behavioral sequelae of latent T. gondii infection have implicated T. gondii seropositivity in the risk for several neuropsychiatric conditions, including depression, disorders associated with autoagression, and psychotic disorders, schizophrenia [17, 18]. Possible associations of chronic T. gondii infection with subclinical behavioral alterations are less well studied and currently discussed [19]; a number of psychomotor and cognitive functions have been suggested to be altered in T. gondii-seropositive individuals [20, 21]

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