MicroRNA-132 dysregulation in Toxoplasma gondii infection has implications for dopamine signaling pathway

Congenital toxoplasmosis and toxoplasmic encephalitis can be associated
with severe neuropsychiatric symptoms. However, which host cell
processes are regulated and how Toxoplasma gondii affects these
changes remain unclear. MicroRNAs (miRNAs) are small noncoding RNA
sequences critical to neurodevelopment and adult neuronal processes by
coordinating the activity of multiple genes within biological networks.
We examined the expression of over 1000 miRNAs in human neuroepithelioma
cells in response to infection with Toxoplasma. MiR-132, a
cyclic AMP-responsive element binding (CREB)-regulated miRNA, was the
only miRNA that was substantially upregulated by all three prototype Toxoplasma strains. The increased expression of miR-132 was also documented in mice following infection with Toxoplasma.
To identify cellular pathways regulated by miR-132, we performed target
prediction followed by pathway enrichment analysis in the transcriptome
of Toxoplasma-infected mice. This led us to identify 20 genes
and dopamine receptor signaling was their strongest associated pathway.
We then examined myriad aspects of the dopamine pathway in the striatum
of Toxoplasma-infected mice 5 days after infection.
Here we report decreased expression of D1-like dopamine receptors (DRD1,
DRD5), metabolizing enzyme (MAOA) and intracellular proteins associated
with the transduction of dopamine-mediated signaling (DARPP-32
phosphorylation at Thr34 and Ser97). Increased concentrations of
dopamine and its metabolites, serotonin (5-HT) and 5-hydroxyindoleacetic
acid were documented by HPLC analysis; however, the metabolism of
dopamine was decreased and 5-HT metabolism was unchanged. Our data show
that miR-132 is upregulated following infection with Toxoplasma
and is associated with changes in dopamine receptor signaling. Our
findings provide a possible mechanism for how the parasite contributes
to the neuropathology of infection.

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