title: MicroRNA-132 dysregulation in Toxoplasma gondii infection has implications for dopamine signaling pathway.
abstract: 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 5days 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.
authors.affiliation: Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA. Electronic address: jxiao4@jhmi.edu.
authors.forename: J
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Psychiatry, Renmin Hospital, Wuhan University, Wuhan, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors.forename: E
authors.initials: E
authors.lastname: Prandovszky
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Karuppagounder
authors.affiliation: Institute for Basic Biomedical Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Talbot
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA.
authors.forename: V L
authors.initials: VL
authors.lastname: Dawson
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Dawson
authors.affiliation: Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Yolken
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000378:metabolism; D018241:Neuroectodermal Tumors, Primitive, Peripheral / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D050641:Receptors, Dopamine D5 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction; D014123:Toxoplasmosis / Q000378:metabolism*; D014124:Toxoplasmosis, Animal / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C547077:MIRN132 microRNA, human; C546976:MIRN132 microRNA, mouse; D035683:MicroRNAs; C497929:Ppp1r1b protein, mouse; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D008995:Monoamine Oxidase; D004298:Dopamine
keywords: Toxoplasma gondii; alteration in expression; dopamine receptor pathway; miR-132; mouse striatum