Biomedical Sciences ETDs

Publication Date

Spring 5-16-2020

Abstract

MicroRNAs are a subcategory of evolutionarily conserved small non-coding RNAs that are altered in psychiatric conditions. The ability of small secretory microvesicles known as exosomes to influence neuronal and glial function via their microRNA (miRNA) cargo has positioned them as a novel and effective method of cell-to-cell communication. Inflammation, which is evident in schizophrenia (SCZ) and bipolar disorder (BD), and antipsychotics usage may alter miRNA expression in the brain. However, little is known about the role of exosome-secreted miRNAs in the regulation of neuronal gene expression and their relevance for SCZ and BD. Here, we used miRNA profiling and qRT-PCR (quantitative real-time PCR) in the orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) of SCZ, BD, and unaffected control subjects, rodent brains and cell culture to measure miRNA and related mRNA expression. We uncovered that miR-223, an inflammation-related and exosome-secreted miRNA that targets glutamate receptors, was increased at the mature miRNA level in the OFC of patients with SCZ as well as BD patients with positive history of psychosis at the time of death and was inversely associated with deficits in the expression of its targets glutamate ionotropic receptor NMDA-type subunit 2B (GRIN2B) and glutamate ionotropic receptor AMPA-type subunit 2 (GRIA2). Additionally, changes in miR-223 levels in the OFC were positively and negatively correlated with inflammatory and GABAergic gene expression, respectively. Intriguingly, no changes in miR-223 mature miRNA levels and miR-223-related mRNAs was observed in the DLPFC of patients with SCZ and BD, despite increases in inflammatory gene expression. Interestingly, miR-223 levels were higher and further increased by maternal immune activation in the prenatal than in adult rat brain. Moreover, miR-223 was found to be enriched in astrocytes and secreted via exosomes, and antipsychotics were shown to control its cellular and exosomal localization in a cell-specific manner. Furthermore, addition of astrocytic exosomes in neuronal cultures resulted in a significant increase in miR-223 expression and a notable reduction in Grin2b and Gria2 mRNA levels, which was strongly inversely associated with miR-223 expression. Remarkably, inhibition of astrocytic miR-223 abrogated the exosomal mediated reduction in neuronal Grin2b levels. Lastly, antipsychotic treatment in astrocytes exacerbated the exosomal miR-223-mediated downregulation of neuronal Grin2b expression. Taken together, our results demonstrate that the exosomal secretion of a psychosis-altered and glial-enriched miRNA that controls neuronal gene expression is regulated by antipsychotics.

Keywords

Exosome, miR-223, glutamate receptor expression, astrocyte, psychosis, antipsychotics

Sponsors

Dedicated Health Research Funds from the University of New Mexico School of Medicine, P20 grant from the NIGMS (1P20GM121176-01)

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Nikolaos Mellios

Second Committee Member

Nora Perrone-Bizzozero

Third Committee Member

Juan Bustillo

Fourth Committee Member

Erin Milligan

Fifth Committee Member

Lauren Jantzie

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