Neurotransmitters and T. gondii
For more than 40 years, it has been known that neurotransmitters are involved in the pathogenesis of schizophrenia. An excess of dopamine has been widely suspected, and along with genetics, dopamine-excess has been one of the most thoroughly researched theories. Despite hundreds of research projects, however, relatively few abnormalities in the dopamine system have ever been identified in individuals with schizophrenia. In recent years, more research attention has been focused on other neurotransmitters, especially glutamate and GABA.
Origin of interest in dopamine and T. gondii
The origin of interest in dopamine and T. gondii appears to have been the 1985 paper by Henry H. Stibbs, Ph.D., then in the School of Public Health and Community Medicine at the University of Washington. Stibbs had been studying trypanosomes and sleeping sickness for 10 years and discovered that this organism increased dopamine level by 34 percent in infected rats.1 He therefore turned his attention to T. gondii because of its known ability to alter learning, memory, and behavior in infected mice and rats. He infected 30 mice with the C56 strain of T. gondii. Ten mice were infected, became symptomatic, and were killed at 12 days (= acute group). Ten mice were infected, treated with sulfadiazine, did not develop symptoms, and were killed at 5 weeks (= chronic group). Ten control mice were also killed at 5 weeks. The brains were assessed neurochemically and compared to the controls. There were no changes in serotonin or 5-HIAA. Norepinephrine was 28 percent decreased in acute but not in chronic infection. Homovanillic acid (HVA) was 40 percent increased in acute but not chronic infection. Dopamine was normal in acute infection but 14 percent increased in the treated mice with chronic infection. Stibbs concluded that T. gondii causes abnormalities in catecholamine metabolism and that these “may be factors contributing to the psychological and motor changes” seen in experimentally infected rodents.2
Toxoplasma gondii has the ability to make dopamine
In 2009, Dr. Glenn McConkey and his colleagues at the University of Leeds in the UK demonstrated that T. gondii has the genes encoding two critical enzymes needed to make dopamine. It has the gene for phenylalanine hydroxylase, which changes phenylalanine to tyrosine, and also the gene for tyrosine hydroxylase, which changes tyrosine to dopa, the precursor of dopamine. These genes were not found in any other closely related parasites except Neospora. McConkey et al. subsequently confirmed that T. gondii does actually make dopamine and showed “a direct correlation between the number of infected cells and the quantity of dopamine released.3 This finding suggests the possibility that the excess dopamine thought to occur in individuals with schizophrenia might be being introduced by T. gondii rather than made by the affected individuals.4 However, doubt was cast on this hypothesis by a study in mice that deleted the two enzyme-encoding genes but this did not change the dopamine levels.15
Effects of changing levels of dopamine on behavior induced by T. gondii infection
Joanne Webster (SMRI grantee) and her colleagues at Oxford infected rats with T. gondii, then treated them with haloperidol, an antipsychotic known to block dopamine. The effect of the haloperidol was to reverse the behavioral effects of T. gondii. They speculated that possible explanatory mechanisms include the ability of haloperidol “to inhibit T. gondii replication and to reduce, directly and indirectly, dopamine levels”.5
Jaroslav Flegr and his colleagues in Prague have studied the effects of T. gondii infection on the behavior of mice. They reported that giving the mice a dopamine reuptake inhibitor (GBR 12909) altered the behavior of the mice and concluded that “the proximal causes of alterations in mice behavior induced by Toxoplasma gondii are probably changes in the dopaminergic system.”6
In other publications, Flegr et al. have speculated that dopamine is the “missing link between schizophrenia and toxoplasmosis,” specifically suggesting that dopamine is increased by activated cytokines (e.g., IL–2) as a consequence of infection.7
Additional studies on the effect of T. gondii on neurotransmitters being carried out in cell cultures in our laboratory have shown a differential effect of different strains on neurotransmitter-related gene expression.8 Toxoplasma infection also has effects on the expression of a number of other genes in neural cell cultures and in experimentally infected mice.
Effects of T. gondii infection on GABA, glutamate and other neurotransmitters
In addition to affecting dopamine, it is now clear that T. gondii may also affect the GABA and glutamate neurotransmitter system. GABA is the principal inhibitory neurotransmitter in the brain and is known to be affected in schizophrenia. In 2012, Fuks et al. in Sweden published a study showing that in mice T. gondii enters the brain and induces an increased production of GABA.9
Additional evidence that T. gondii affects the GABAergic system was shown by a study of seizures in rodents.10 A previously cited study on the effects of T. gondii infections on juvenile and adult mice also reported that T. gondii affects not only dopamine and GABA, but glutamate, serotonin and norepinephrine as well.11 Research linking T. gondii to NMDA and the glutmate systemh has become especially interesting.16,17
Good reviews of the effects of T. gondii on neurotransmitters can be found in Fabiani et al.12
Effect of T. gondii on endogenous retroviruses
It is increasingly clear that endogenous retroviruses, embedded in the human genome, can affect the expression of genes. Studies in cell cultures have demonstrated that T. gondii can influence of transcription of endogenous retroviruses. This is another possible mechanism by which this parasite might alter human behavior.13
Strain differences in effects on neurotransmitters
A study reported that 3 strains of T. gondii (types I, II, and III) exerted significantly different effects on dopamine, glutamate, and serotonin as well as on 2 neuropeptides.14
- Stibbs HH. Neurochemical and activity changes in rats infected with Trypanosoma brucei gambiense. J Parasitology. 1984;70:428–432.
- Stibbs HH. Changes in brain concentrations of catecholamines and indoleamines in Toxoplasma gondii infected mice. Ann Trop Med Parasitol. 1985;79:153–157, copyright 1985, Maney Publishing, www.maney.co.uk/journals/atmp; linked to PDF file with permission.
- Prandovszky E, Gaskell E, Martin H, et al. The neurotropic parasite Toxoplasma gondii increases dopamine metabolism. PLoS One. 2011;6:e23866.
- Gaskell EA, Smith JE, Pinney JW, et al. A unique dual activity amino acid hydroxylase in Toxoplasma gondii. PLoS One. 2009;4:e4801.
- Webster JP, Lamberton PHL, Donnelly CA, et al. Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii’s ability to alter host behavior.Proc R Soc B. 2006;273:1023–1030, copyright 2006, the Royal Society; linked to PDF file with permission.
- Skallová A, Kodym P, Frynta D, et al. The role of dopamine in Toxoplasma-induced behavioural alterations in mice: an etiological and ethnopharmacological study. Parasitology. 2006;133:525–535.
- Flegr J, Preiss M, Klose J, et al. Decreased level of psychobiological factor novelty seeking and lower intelligence in men latently infected with the protozoan parasite Toxoplasma gondii : dopamine, a missing link between schizophrenia and toxoplasmosis? Biol Psychol. 2003;63:253–268; Flegr J. Effects of Toxoplasma on human behavior. Schizophr Bull. 2007;33:757–760.
- Xiao J, Li Y, Jones-Brando L, Yolken RH. Abnormalities of neurotransmitter and neuropeptide systems in human neuroepithelioma cells infected by three Toxoplasma strains. J Neural Transm. 2013;120:1631-9.
- Fuks JM, Arrighi RB, Weidner JM, et al. GABAergic signaling is linked to a hypermigratory phenotype in dendritic cells infected by Toxoplasma gondii. PLoS Pathog. 2012;8:e1003051.
- Brooks JM et al. Toxoplasma gondii infections alter GABAergic synapses and signaling in the central nervous system. 2015; 6(6): e1428-15.
- Kannan G., et al. Anti-NMDA receptor autoantibodies and associated neurobehavioral pathology in mice are dependent on age of first exposure to Toxoplasma gondii. Neurobiology of Disease. 2016. Doi: 10.1016/j.nbd.2016.03.005.
- Fabiania S, et al. Neurobiological studies on the relationship between toxoplasmosis and neuropsychiatric diseases. Journal of the Neurological Sciences 2015; doi: 10.1016/j.jns.2015.02.028;Elsheikha HM, Busselberg D, Zhu X-Q. The known and missing links between Toxoplasma gondii and schizophrenia. Metab Brain Dis. 2016. doi: 10.1007/s11011-016-9822-1.
- Frank O et al. Altered transcriptional activity of human endogenous retroviruses in neuroepithelial cells infection with toxoplasma gondii. J Infect Dis. 2006; 194(10): 1447-9.
- Xiao J, Li Y, Jones-Brando, L. Abnormalities of neurotransmitters and neuropeptide systems in human neuroepithelioma cells infects by three Toxoplasma strains. 2013. J Neural Transm. 120: 1631-1639.
- McFarland R, et al. AAH2 gene is not required for dopamine-dependent neurochemical and behavioral abnormalities produced by Toxoplasma infection in mouse. Behavioral Brain Research. 2018; 347″ 193-200.
- Li Y, et al. Chronic Toxoplasma infection induces anti-NMDA receptor autoantibodies and associated behavioral changes and neuropathology. Infect Immune. 2018. doi: 10.1128/IAI.00398-18.
- Xiao J, et al. Toxoplasma gondii: Biological parameters of the connection to schizophrenia. Schizophrenia Bulletin. 2018. doi: 10.1093/schbul/sby082.