Downregulation of the central noradrenergic system by Toxoplasma gondii infection

The parasitic protozoan Toxoplasma gondiibecomes encysted in brain and muscle tissue during chronic infection, a stage that was previously thought to be dormant but has been found to be active and associated with physiological effects in the host. Dysregulation of catecholamines in the CNS has previously been observed in chronically-infected animals. In the study described here, the noradrenergic system was suppressed with decreased levels of norepinephrine in brains of infected animals and in infected neuronal cells in vitro. Expression of dopamine b-hydroxylase (DBH), essential for synthesis of norepinephrine from dopamine, was the most differentially-expressed gene in infections in vitroand was down-regulated in infected brain tissue, particularly in the prefrontal cortex and dorsal locus coeruleus/pons region. The down-regulated DBH expression in infected rat catecholaminergic and human neuronal cells corresponded with decreased norepinephrine and increased dopamine. As the DBH suppression was observed in vitro, this effect is not caused by neuroinflammation. Silencing of DBH expression was specific for T. gondiiinfection and was not observed with CMV infection. The noradrenergic-linked behaviors of sociability and arousal were altered in chronically-infected animals, with a high correlation between DBH expression and infection intensity. These findings together provide a plausible mechanism to explain prior discrepancies in changes to CNS neurotransmitters levels with infection. The suppression of norepinephrine synthesis observed here may, in part, explain behavioural effects of infection, associations with mental illness, and neurological consequences of infection such as the loss of coordination and motor impairments associated with human toxoplasmosis.