A Proposed Mechanism for Cerebral Toxoplasmosis as a Contributing Factor in Schizophrenia

Abstract

Schizophrenia is a devastating mental disorder that affects around 1% of the world’s population, characterized by the presence of positive symptoms including hallucinations and delusions, negative symptoms including depression and anxiety, and cognitive impairment including deficits in speech and memory. The complete etiology of schizophrenia is not yet understood, though it is known that both genetics and environmental factors play a role. One environmental factor, a chronic cerebral infection by the parasite Toxoplasma gondii, has one of the highest correlations with schizophrenia of any environmental factor, and may play a role in the pathology of the disease. This is especially true in the case of Type I toxoplasma, which is the most virulent of the three common strains of the parasite. Toxoplasmosis causes an increase in dopamine levels in the striatum and substantia nigra through the production of two enzymes that mimic the rate limiting enzyme in dopamine synthesis, tyrosine hydroxylase. Increased dopamine concentrations in these areas are experimentally correlated with positive schizophrenia symptoms. In addition, toxoplasmosis causes chronic upregulation of the kynurenine pathway via INF- release, leading to chronically elevated kynurenic acid levels. This leads to dysfunction of the glutamatergic system via (1) the binding and inhibition ofα7- nicotinic receptors, leading to decreased GABAergic inhibitory activity in the hippocampus and decreased glutamate release in the prefrontal cortex, and (2) NMDA and AMPA receptor hypofunction, causing decreased inhibitory signaling by GABAergic neurons leaving glutamatergic neurons in a hyper-excitable state. These mechanisms, compounded by commonly identified mutations in the genes of schizophrenic individuals affecting the dopaminergic system, the kynurenine pathway,α7-nicotinic receptors, and the glutamatergic system, create a viable theory as to how the interplay between genetics and toxoplasmosis could cause schizophrenia.