Neuroscience. 2014 Mar 18. pii: S0306-4522(14)00221-8. doi: 10.1016/j.neuroscience.2014.03.015. [Epub ahead of print]

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

Xiao J¹, Li Y², Prandovszky E³, Karuppagounder SS⁴, Talbot CC Jr⁵, Dawson VL⁶, Dawson TM⁷, Yolken RH³.

 

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 and 5-hydroxyindoleacetic acid were documented by HPLC analysis; however, the metabolism of dopamine was decreased and serotonin 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.
Copyright © 2014. Published by Elsevier Ltd.

KEYWORDS:

Alteration in expression, Dopamine receptor pathway, Mouse striatum, Toxoplasma gondii, miR-132

PMID:

24657774

[PubMed - as supplied by publisher]