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TY - JOUR AU - Shaltiel, G. AU - Hanan, M. AU - Wolf, Y. AU - Barbash, S. AU - Kovalev, E. AU - Shoham, S. AU - Soreq, H. PY - 2013 DA - 2013/01/01 TI - Hippocampal microRNA-132 mediates stress-inducible cognitive deficits through its acetylcholinesterase target JO - Brain Structure and Function SP - 59 EP - 72 VL - 218 IS - 1 AB - 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. SN - 1863-2661 UR - https://doi.org/10.1007/s00429-011-0376-z DO - 10.1007/s00429-011-0376-z ID - Shaltiel2013 ER -