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

J Neuroinflammation. 2018 Aug 1;15(1):216. doi: 10.1186/s12974-018-1242-1.

Abstract

Background: 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.

Methods: Here, 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.

Results: A 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.

Conclusion: These 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.

Keywords: Chronic Toxoplasma infection; Neuroinflammation; Synaptic proteins; Toxoplasma gondii.

MeSH terms

  • Animals
  • Antiprotozoal Agents / pharmacology
  • Brain / metabolism*
  • Chronic Disease
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Glutamic Acid / metabolism
  • Mass Spectrometry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Meta-Analysis as Topic
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Proteomics
  • RNA, Messenger / metabolism
  • Sulfadiazine / pharmacology
  • Synapses / metabolism*
  • Synapses / pathology
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism*
  • Tandem Mass Spectrometry
  • Toxoplasma / pathogenicity
  • Toxoplasmosis, Animal / pathology*

Substances

  • Antiprotozoal Agents
  • Cytokines
  • Membrane Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Sulfadiazine
  • Glutamic Acid

Grant support