Downregulation of the Central Noradrenergic System by Toxoplasma gondii Infection

Abstract

Toxoplasma gondii is associated with physiological effects in the host. Dysregulation of catecholamines in the central nervous system has previously been observed in chronically infected animals. In the study described here, the noradrenergic system was found to be suppressed with decreased levels of norepinephrine (NE) in brains of infected animals and in infected human and rat neural cells in vitro. The mechanism responsible for the NE suppression was found to be downregulation of dopamine ␤-hydroxylase (DBH) gene expression, encoding the enzyme that synthesizes norepinephrine from dopamine, with downregulation observed in vitro and in infected brain tissue, particularly in the dorsal locus coeruleus/pons region. The downregulation was sex specific, with males expressing reduced DBH mRNA levels whereas females were unchanged. Rather, DBH expression correlated with estrogen receptor in the female rat brains for this estrogen-regulated gene. DBH silencing was not a general response of neurons to infection, as human cytomegalovirus did not downregulate DBH expression. The noradrenergic-linked behaviors of sociability and arousal were altered in chronically infected animals, with a high correlation between DBH expression and infection intensity. A decrease in DBH expression in noradrenergic neurons can elevate dopamine levels, which provides a possible explanation for mixed observations of changes in this neurotransmitter with infection. Decreased NE is consistent with the loss of coordination and motor impairments associated with toxoplasmosis. Further, the altered norepinephrine synthesis observed here may, in part, explain behavioral effects of infection and associations with mental illness.

Impact of Toxoplasma gondii Infection on Host Non-coding RNA Responses

“…These combined results suggest that miR-132 may be a common target of a broad range of pathogens and may represent a general response to infection. It is also worth noting that other researchers have reported dysregulation of dopamine pathways during Toxoplasma infection, suggesting possible links to nervous system abnormalities (Syn et al, 2018; Alsaady et al, 2019).…”

Epigenetic Manipulation of Psychiatric Behavioral Disorders Induced by Toxoplasma gondii

“…Moreover, the fact that anomalous accumulation of dopamine between synapses could cause various pathological processes such as increased dopamine concentration, synaptic structure disorder, proliferation of neural progenitor cells, and migration of neuron cells (Ortiz-Guerrero et al, 2020), thus may lead to the occurrence of psychiatric behavioral disorders. Alsaady et al (2019) also found that T. gondii could regulate the expression of dopamine b-hydroxylase (DBH) gene, which is responsible for dopamine synthesis of NE, resulting in a decrease in NE concentration in human/rat neurons that were cultured in vitro and were infected with tachyzoites, but the decrease in NE in rat brain tissue was limited in males. The authors also demonstrated that this sexspecific downregulation of DBH was associated with host behavioral changes.…”

“…Additionally, the expression of dopamine β-hydroxylase (DBH), an enzyme that converts DA to NE, was specifically downregulated in the infected cells and male mice brain tissues. It leads to the suppression of NE and alternation of sociability and arousal ( Alsaady et al., 2019 ). In particularly, reduction in DBH may be a specific neuron response to T. gondii infection, since human cytomegalovirus could not induce similar downregulation of DBH.…”

Neuroimmunology of Common Parasitic Infections in Africa

“…It has been proposed that an interplay between neuroinflammation and neurotransmission may underlie cognitive changes associated with chronic toxoplasmosis (160). Indeed, reported neurotransmission alterations during toxoplasmosis in rodents include dysregulations of catecholamines, GABA and glutamate (161)(162)(163).…”