Changes in brain MicroRNAs contribute to cholinergic stress reactions.
Mental stress modifies both cholinergic neurotransmission and alternative splicing in the brain, via incompletely understood mechanisms. Here, we report that stress changes brain microRNA (miR) expression and that some of these stress-regulated miRs regulate alternative splicing. Acute and chronic immobilization stress differentially altered the expression of numerous miRs in two stress-responsive regions of the rat brain, the hippocampal CA1 region and the central nucleus of the amygdala. miR-134 and miR-183 levels both increased in the amygdala following acute stress, compared to unstressed controls. Chronic stress decreased miR-134 levels, whereas miR-183 remained unchanged in both the amygdala and CA1. Importantly, miR-134 and miR-183 share a common predicted mRNA target, encoding the splicing factor SC35. Stress was previously shown to upregulate SC35, which promotes the alternative splicing of acetylcholinesterase (AChE) from the synapse-associated isoform AChE-S to the, normally rare, soluble AChE-R protein. Knockdown of miR-183 expression increased SC35 protein levels in vitro, whereas overexpression of miR-183 reduced SC35 protein levels, suggesting a physiological role for miR-183 regulation under stress. We show stress-induced changes in miR-183 and miR-134 and suggest that, by regulating splicing factors and their targets, these changes modify both alternative splicing and cholinergic neurotransmission in the stressed brain.
Meerson
Ari
A
Department of Biological Chemistry, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel.
Cacheaux
Luisa
L
Goosens
Ki Ann
KA
Sapolsky
Robert M
RM
Soreq
Hermona
H
Kaufer
Daniela
D
D000110:Acetylcholinesterase / Q000235:genetics* / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics*; D000679:Amygdala / Q000201:enzymology / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D056547:CA1 Region, Hippocampal / Q000201:enzymology / Q000503:physiopathology; D016466:CHO Cells; D002908:Chronic Disease / Q000523:psychology; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D051381:Rats; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D013315:Stress, Psychological / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology
D005819:Genetic Markers; D007527:Isoenzymes; D035683:MicroRNAs; C543802:Mirn183 microRNA, mouse; D009687:Nuclear Proteins; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D000110:Acetylcholinesterase