Exosomal secretion of a psychosis-altered miRNA that regulates glutamate receptor expression is affected by antipsychotics.


FULLTEXT
Published:
11.28.2019
|
Last Revised:
03.27.2020
PMID:
31775160
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Journal Article,Research Support, N.I.H., Extramural

Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.,Autophagy inflammation and metabolism (AIM) center, Albuquerque, NM, USA.
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
Center for Genomic Medicine, Chemical Neurobiology Laboratory, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.,Center for Experimental Drugs and Diagnostics, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.,Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Laboratory of Brain Research, Stanley Medical Research Institute, Chevy Chase, MD, USA.
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA. nmellios@salud.unm.edu.,Autophagy inflammation and metabolism (AIM) center, Albuquerque, NM, USA. nmellios@salud.unm.edu.

Abstract

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. However, little is known about the role of exosome-secreted miRNAs in the regulation of glutamate receptor gene expression and their relevance for schizophrenia (SCZ) and bipolar disorder (BD). Using mature miRNA profiling and quantitative real-time PCR (qRT-PCR) in the orbitofrontal cortex (OFC) of SCZ (N = 29; 20 male and 9 female), BD (N = 26; 12 male and 14 female), and unaffected control (N = 25; 21 male and 4 female) subjects, we uncovered that miR-223, an exosome-secreted miRNA that targets glutamate receptors, was increased at the mature miRNA level in the OFC of SCZ and 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). Furthermore, changes in miR-223 levels in the OFC were positively and negatively correlated with inflammatory and GABAergic gene expression, respectively. 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. Lastly, inhibition of astrocytic miR-223 abrogated the exosomal-mediated reduction in 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.

| |