TY - JOUR
T1 - Hippocampal microRNA-132 mediates stress-inducible cognitive deficits through its acetylcholinesterase target
AU - Shaltiel, G.
AU - Hanan, M.
AU - Wolf, Y.
AU - Barbash, S.
AU - Kovalev, E.
AU - Shoham, S.
AU - Soreq, H.
N1 - Funding Information:
The authors are grateful to Drs. O. Cohen and G. Zimmerman (Jerusalem) for their contribution to this study. Also acknowledged is support by the Israel Science Foundation Legacy Heritage Biomedical Science Partnership (Grant No. 378/11), the Gatsby Foundation and the German Research Foundation Trilateral Cooperation Program (to H.S.). G.S. was the incumbent of an Eshkol post-doctoral fellowship by the Israel Ministry of Science, M.H. and S.B. were both awarded pre-doctoral fellowships by the Edmond and Lily Safra Center for Brain Sciences.
PY - 2013/1
Y1 - 2013/1
N2 - 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.
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.
KW - Acetylcholinesterase
KW - Cholinergic
KW - Cognition
KW - MicroRNA-132
KW - P250GAP
KW - Psychological stress
UR - http://www.scopus.com/inward/record.url?scp=84872293448&partnerID=8YFLogxK
U2 - 10.1007/s00429-011-0376-z
DO - 10.1007/s00429-011-0376-z
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C2 - 22246100
AN - SCOPUS:84872293448
SN - 1863-2653
VL - 218
SP - 59
EP - 72
JO - Brain Structure and Function
JF - Brain Structure and Function
IS - 1
ER -