Hippocampal microRNA-132 mediates stress-inducible cognitive deficits through its acetylcholinesterase target

• Published in: Brain Structure and Function 2013-01, Vol.218 (1), p.59-72
• Main Authors: Shaltiel, G., Hanan, M., Wolf, Y., Barbash, S., Kovalev, E., Shoham, S., Soreq, H.
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; Acetylcholinesterase - genetics; Acetylcholinesterase - metabolism; Animals; Binding Sites; Biomedical and Life Sciences; Biomedicine; Brain; Cell Biology; Cells, Cultured; Cognition - drug effects; Cognition Disorders - enzymology; Cognition Disorders - etiology; Cognition Disorders - genetics; Cognition Disorders - prevention & control; Cognition Disorders - psychology; Cognitive ability; Down-Regulation; Electroshock - psychology; Enzymes; Female; Gene Expression Regulation, Enzymologic; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Hippocampus - drug effects; Hippocampus - enzymology; Lentivirus; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs; MicroRNAs - metabolism; Motor Activity; Muscarinic Agonists - pharmacology; Neurochemistry; Neurology; Neurosciences; Original; Original Article; Pilocarpine - pharmacology; Predatory Behavior; RNA Interference; RNA, Messenger - metabolism; Stress; Stress, Psychological - complications; Stress, Psychological - enzymology; Stress, Psychological - genetics; Stress, Psychological - psychology; Synapses - enzymology; Transfection; Up-Regulation
• ISSN: 1863-2653; 1863-2661; 0340-2061
• DOI: 10.1007/s00429-011-0376-z

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.