title: Hippocampal microRNA-132 mediates stress-inducible cognitive deficits through its acetylcholinesterase target.
abstract: Diverse stress stimuli induce long-lasting cognitive deficits, but the underlying molecular mechanisms are still incompletely understood. Here, we report three different stress models demonstrating that stress-inducible increases in microRNA-132 (miR-132) and consequent decreases in its acetylcholinesterase (AChE) target are causally involved. In a mild model of predator scent-induced anxiety, we demonstrate long-lasting hippocampal elevation of miR-132, accompanied by and associated with reduced AChE activity. Using lentiviral-mediated suppression of "synaptic" AChE-S mRNA, we quantified footshock stress-inducible changes in miR-132 and AChE and its corresponding cognitive damages. Stressed mice showed long-lasting impairments in the Morris water maze. In contrast, pre-stress injected AChE-suppressing lentivirus, but not a control virus, reduced hippocampal levels of both miR-132 and AChE and maintained similar cognitive performance to that of naïve, non-stressed mice. To dissociate between miR-132 and synaptic AChE-S as potential causes for stress-inducible cognitive deficits, we further used engineered TgR mice with enforced over-expression of the soluble "readthrough" AChE-R variant without the 3'-untranslated region binding site for miR-132. TgR mice displayed excess AChE-R in hippocampal neurons, enhanced c-fos labeling and correspondingly intensified reaction to the cholinergic agonist pilocarpine. They further showed excessive hippocampal expression of miR-132, accompanied by reduced host AChE-S mRNA and the GTPase activator p250GAP target of miR-132. At the behavioral level, TgR mice showed abnormal nocturnal locomotion patterns and serial maze mal-performance in spite of their reduced AChE-S levels. Our findings attribute stress-inducible cognitive impairments to cholinergic-mediated induction of miR-132 and consequently suppressed ACHE-S, opening venues for intercepting these miR-132-mediated damages.
authors.affiliation: Edmond and Lily Safra Center of Brain Sciences, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Shaltiel
authors.forename: M
authors.initials: M
authors.lastname: Hanan
authors.forename: Y
authors.initials: Y
authors.lastname: Wolf
authors.forename: S
authors.initials: S
authors.lastname: Barbash
authors.forename: E
authors.initials: E
authors.lastname: Kovalev
authors.forename: S
authors.initials: S
authors.lastname: Shoham
authors.forename: H
authors.initials: H
authors.lastname: Soreq
mesh_terms: D020413:3' Untranslated Regions; D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control / Q000523:psychology; D015536:Down-Regulation; D004597:Electroshock / Q000523:psychology; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D009043:Motor Activity; D018721:Muscarinic Agonists / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D011235:Predatory Behavior; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000523:psychology; D013569:Synapses / Q000201:enzymology; D014162:Transfection; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; D058851:GPI-Linked Proteins; D020690:GTPase-Activating Proteins; C546976:MIRN132 microRNA, mouse; D035683:MicroRNAs; D018721:Muscarinic Agonists; D012333:RNA, Messenger; C085379:rho GTPase-activating protein; D010862:Pilocarpine; D000110:Acetylcholinesterase; C548245:Ache protein, mouse