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

Brain Struct Funct. 2013 Jan;218(1):59-72. doi: 10.1007/s00429-011-0376-z. Epub 2012 Jan 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Acetylcholinesterase / genetics
  • Acetylcholinesterase / metabolism*
  • Animals
  • Binding Sites
  • Cells, Cultured
  • Cognition Disorders / enzymology
  • Cognition Disorders / etiology*
  • Cognition Disorders / genetics
  • Cognition Disorders / prevention & control
  • Cognition Disorders / psychology
  • Cognition* / drug effects
  • Down-Regulation
  • Electroshock / psychology
  • Female
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism
  • Gene Expression Regulation, Enzymologic
  • Hippocampus / drug effects
  • Hippocampus / enzymology*
  • Male
  • Maze Learning
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / metabolism*
  • Motor Activity
  • Muscarinic Agonists / pharmacology
  • Pilocarpine / pharmacology
  • Predatory Behavior
  • RNA Interference
  • RNA, Messenger / metabolism
  • Stress, Psychological / complications*
  • Stress, Psychological / enzymology
  • Stress, Psychological / genetics
  • Stress, Psychological / psychology
  • Synapses / enzymology
  • Transfection
  • Up-Regulation


  • 3' Untranslated Regions
  • GPI-Linked Proteins
  • GTPase-Activating Proteins
  • MIRN132 microRNA, mouse
  • MicroRNAs
  • Muscarinic Agonists
  • RNA, Messenger
  • rho GTPase-activating protein
  • Pilocarpine
  • Acetylcholinesterase
  • Ache protein, mouse