TY - JOUR
T1 - Exosomal secretion of a psychosis-altered miRNA that regulates glutamate receptor expression is affected by antipsychotics
AU - Amoah, Stephen K.
AU - Rodriguez, Brian A.
AU - Logothetis, Constantine N.
AU - Chander, Praveen
AU - Sellgren, Carl M.
AU - Weick, Jason P.
AU - Sheridan, Steven D.
AU - Jantzie, Lauren L.
AU - Webster, Maree J.
AU - Mellios, Nikolaos
N1 - Funding Information:
This work was supported by a mentored PI grant as part of a P20 grant from the NIGMS (1P20GM121176-01—N.M. and S.K.A.). We would like to thank the SMRI brainbank for providing us with postmortem brain specimen, Colleen Ramsower and Crystal Richt at the University of Arizona Genetics Core for assistance in miRNA profiling, Mathew Campen and Tamara Young for help with NanoSight, Tamara Howard for EM assistance, Evelyn Lozano, and Eunice Amoah for technical assistance, and Nora Perrone-Bizzozero, Erin Milligan, Juan Bustillo, and Andrea Allan for useful advice and feedback. This work was supported in part by Dedicated Health Research Funds from the University of New Mexico School of Medicine (N.M). The authors declare no competing interests.
Publisher Copyright:
© 2019, The Author(s).
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41386-019-0579-1
DO - 10.1038/s41386-019-0579-1
M3 - Article
C2 - 31775160
AN - SCOPUS:85076523710
VL - 45
SP - 656
EP - 665
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 4
ER -