This is a new RO1 grant application seeking to gain a better understanding of the role of noncoding RNA regulatory networks relating to the NMDA receptor (NMDA-R) hypofunction hypothesis in schizophrenia. The underlying hypothesis of this application is that specific miRNAs or families of miRNAs play a role in regulating schizophrenia-like behavioral deficits in mice. The goals of this proposal are threefold: First, we will investigate expression patterns of brain-specific microRNAs (miRNAs) in NMDA-R- related animal models of schizophrenia. Specifically, we will examine in mice the effects of acute or chronic exposure to the non-competitive NMDA-R antagonist and schizomimetic agent, MK-801, on miRNA expression in brain regions implicated in schizophrenia in human patients, with a focus on prefrontal cortex (PFC). It is predicted that pharmacological and genetic models of schizophrenia in mice will be associated with distinct patterns of dysregulated miRNA expression. Importantly, convergent data between pharmacological and genetic models of schizophrenia will provide convergent support for the participation of particular miRNAs or families of miRNAs in schizophrenia-related deficits. Importantly, we will examine the effects of agents with known beneficial effects on schizophrenia-associated behavioral deficits (haloperidol and clozapine) on the expression of miRNAs shown to be dysregulated in the schizomimetic mouse models. It is predicted that antipsychotic agents with known clinical utility will reverse, at least in part, dysregulated patterns of miRNA expression in the mouse models of schizophrenia. To more directly assess the roles of identified miRNAs in schizophrenia-like behavioral deficits in mice, we will modulate the expression of targeted miRNAs by direct intracerebral infusion of locked nucleic acid (LNA)-modified antagomiRs into the brains of mice. The effects of modulating targeted miRNAs in this manner will be assessed on baseline and MK-801-induced behaviors in three procedures that model aspects of schizophrenia-like deficits in mice: hyperlocomotion with stereotyped behaviors;decreases in social interaction;and elevations of intracranial self-stimulation thresholds. It is predicted that miRNAs mediate the expression of schizophrenia-like deficits in mice and that decreasing the expression of targeted miRNAs may attenuate the expression of schizophrenia-like deficits. The experiments proposed in this application promise to yield significant new insights into the pathophysiology of schizophrenia, and may reveal novel treatment and/or biomarker approaches for schizophrenia-associated behavioral deficits.
TO PUBLIC HEALTH: Schizophrenia is a chronic psychiatric disorder characterized by impairments in perception or expression of reality, by significant social or occupational dysfunction and by profound cognitive impairment. Thus, schizophrenia results in tremendous human suffering and negative economic impact on society. Approximately 1% of the population of the United States, around 3 million people, suffers from schizophrenia. Importantly, the underlying etiology of schizophrenia remains largely unknown and there is a marked need for improved treatment paradigms. The proposed work has the potential to aid in the development of completely novel therapeutics.
|Khorkova, O; Hsiao, J; Wahlestedt, C (2015) Basic biology and therapeutic implications of lncRNA. Adv Drug Deliv Rev 87:15-24|
|St Laurent, Georges; Wahlestedt, Claes; Kapranov, Philipp (2015) The Landscape of long noncoding RNA classification. Trends Genet 31:239-51|
|Khorkova, Olga; Myers, Amanda J; Hsiao, Jane et al. (2014) Natural antisense transcripts. Hum Mol Genet 23:R54-63|
|Halley, Paul; Kadakkuzha, Beena M; Faghihi, Mohammad Ali et al. (2014) Regulation of the apolipoprotein gene cluster by a long noncoding RNA. Cell Rep 6:222-30|
|Halley, Paul; Khorkova, Olga; Wahlestedt, Claes (2013) Natural antisense transcripts as therapeutic targets. Drug Discov Today Ther Strateg 10:e119-e125|
|Ozomaro, Uzoezi; Wahlestedt, Claes; Nemeroff, Charles B (2013) Personalized medicine in psychiatry: problems and promises. BMC Med 11:132|
|Magistri, Marco; Faghihi, Mohammad Ali; St Laurent 3rd, Georges et al. (2012) Regulation of chromatin structure by long noncoding RNAs: focus on natural antisense transcripts. Trends Genet 28:389-96|
|Miller, Brooke H; Wahlestedt, Claes (2010) MicroRNA dysregulation in psychiatric disease. Brain Res 1338:89-99|
|Kocerha, Jannet; Faghihi, Mohammad Ali; Lopez-Toledano, Miguel A et al. (2009) MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc Natl Acad Sci U S A 106:3507-12|