Manipulation of the brain by microscopic parasite may provide insight to schizophrenia
Many of us commonly associate the risk of developing neurological diseases such as depression and schizophrenia with genetic and lifestyle factors, for example drug abuse.
Yet, as recently described in Science (doi:10.1126/science.aax0169), a new study of 80,000 Danish blood donors found that those testing positive for infection with the single-celled organism T. gondii were 2.5 times more likely to develop schizophrenia. Indeed, T. gondii infection has been correlated with schizophrenia in more than 100 studies (Arias et al., 2012, Torrey et al., 2012).The microscopic parasite, Toxoplasma gondii, infiltrates the brain and neurons, forming tissue cysts, from which it orchestrates the behaviour of its host. Indeed, T. gondii is known for inverting rodent’s fear of cats to attraction. Infection initiates a series of complex alterations to the nervous system including modifications to neurotransmitters – the nervous system’s chemical communicators (Tyebji et al., 2019). A recent study by G. McConkey’s team at the University of Leeds has found that infection greatly decreases levels of norepinephrine, also known as noradrenaline, a key neurotransmitter in the brain (Alsaady et al., 2019).
By examining gene expression in rodent brains and human and rat neuronal cells grown in the lab, the gene responsible for producing norepinephrine from the neurotransmitter dopamine was found to be severely suppressed during infection. Lowered levels of this gene, the dopamine β-hydroxylase (DBH) gene, results in the accumulation of dopamine and a deficiency of norepinephrine within neurons. Previous studies by the same group showed that Toxoplasma gondii infection could increase dopamine levels within neurons and so these new findings suggest a mechanism through which this is, at least partially, achieved (Prandovszky et al., 2011). Schizophrenia is a complex disease of unknown cause however, alterations to the functioning of various neurotransmitters have been linked to schizophrenia, with changes to the dopaminergic system representing the bulk of published data. This new research therefore promises to aid our understanding into the mechanism by which schizophrenia develops and consequently may inform future research into the treatment of the disease.
Intriguingly, despite the low number of neurons infected, the DBH gene was down-regulated greater than 30-fold in the brain. At present it remains a mystery as to how the parasite invokes such widespread alterations. One possibility, is that Toxoplasma gondii secretes some form of compound into the circulation of the host, permitting changes in uninfected neurons in addition to infected cells. Current ongoing research aims to explore how exactly the parasite elicits this global suppression of the noradrenergic system.
References
ALSAADY, I., TEDFORD, E., ALSAAD, M., BRISTOW, G., KOHLI, S., MURRAY, M., REEVES, M., VIJAYABASKAR, M. S., CLAPCOTE, S. J., WASTLING, J. & MCCONKEY, G. A. 2019. Downregulation of the Central Noradrenergic System by Toxoplasma gondii Infection. Infection and Immunity, 87, e00789-18.
ARIAS, I., SORLOZANO, A., VILLEGAS, E., LUNA, J. D. D., MCKENNEY, K., CERVILLA, J., GUTIERREZ, B. & GUTIERREZ, J. 2012. Infectious agents associated with schizophrenia: A meta-analysis. Schizophrenia Research, 136, 128-136.
PRANDOVSZKY, E., GASKELL, E., MARTIN, H., DUBEY, J. P., WEBSTER, J. P. & MCCONKEY, G. A. 2011. The Neurotropic Parasite Toxoplasma gondii Increases Dopamine Metabolism. PLOS ONE, 6, e23866.
TORREY, E.F., BARTKO, J.J., & YOLKEN, R.H. 2012. Toxoplasma gondii and Other Risk Factors for Schizophrenia: An Update. Schizophr Bull. 38, 642–647.
TYEBJI, S., SEIZOVA, S., HANNAN, A. J. & TONKIN, C. J. 2019. Toxoplasmosis: A pathway to neuropsychiatric disorders. Neuroscience & Biobehavioral Reviews, 96, 72-92.
Further information
Access the recent publication by McConkey et al., "Downregulation of the Central Noradrenergic System by Toxoplasma gondii Infection" at: https://iai.asm.org/content/iai/87/2/e00789-18.full.pdf
Contacts:
Glenn McConkey: G.A.McConkey@leeds.ac.uk
Adam Tarver: bs15a2t@leeds.ac.uk
