MicroRNA Loss Enhances Learning and Memory in Mice

Abstract

Dicer-dependent noncoding RNAs, including microRNAs (miRNAs), play an important role in a modulation of translation of mRNA transcripts necessary for differentiation in many cell types. In vivo experiments using cell type-specific Dicer1 gene inactivation in neurons showed its essential role for neuronal development and survival. However, little is known about the consequences of a loss of miRNAs in adult, fully differentiated neurons. To address this question, we used an inducible variant of the Cre recombinase (tamoxifeninducible CreERT2) under control of Camk2a gene regulatory elements. After induction of Dicer1 gene deletion in adult mouse forebrain, we observed a progressive loss of a whole set of brain-specific miRNAs. Animals were tested in a battery of both aversively and appetitively motivated cognitive tasks, such as Morris water maze, IntelliCage system, or trace fear conditioning. Compatible with rather long half-life of miRNAs in hippocampal neurons, we observed an enhancement of memory strength of mutant mice 12 weeks after the Dicer1 gene mutation, before the onset of neurodegenerative process. In acute brain slices, immediately after high-frequency stimulation of the Schaffer collaterals, the efficacy at CA3-to-CA1 synapses was higher in mutant than in control mice, whereas long-term potentiation was comparable between genotypes. This phenotype was reflected at the subcellular and molecular level by the elongated filopodia-like shaped dendritic spines and an increased translation of synaptic plasticity-related proteins, such as BDNF and MMP-9 in mutant animals. The presented work shows miRNAs as key players in the learning and memory process of mammals.

MicroRNAs and synaptic plasticity—a mutual relationship

“…These effects are also supported electrophysiologically by an increase in the post-tetanic potentiation at Sc-CA1 synapses. LTP or basal synaptic transmission is however not affected in these mice, suggesting that synaptic alterations might not be the only cause for the observed behavioural phenotypes [56].…”

“…Conditional inactivation of Dicer in the forebrain leads to a decrease in the size of hippocampal and cortical regions as well as an increase in the size of lateral ventricles in mice [55,77]. Expectedly, the level of several miRNAs is reduced as a result of Dicer loss in the mouse forebrain [55,56].…”

Trans-activation Response (TAR) RNA-binding Protein 2 Is a Novel Modulator of Transient Receptor Potential Canonical 4 (TRPC4) Protein

“…MicroRNAs, a class of noncoding RNAs, are capable of regulating mRNA translation by various mechanisms (28) and, thereby, are also elements for the regulation of plasticity-related mRNAs by neurons (53). By the mechanism suggested above, Dicer activity could be dynamically regulated in neurons that do express TRPC4 and TRPC5 and induce profound changes in neuronal plasticity given the slow turnover rates of Dicer-dependent noncoding RNAs in these cells (54).…”

Advances in MicroRNAs and Alzheimer’s Disease Research

“…How up-regulation of a subset of miRNAs modulates gene expression pathways during several phases of learning and memory? A new work showing miRNAs as key players in the learning and memory process of mammals, was published by (Konopka et al, 2010). In a mouse model with an inducible disruption of the Dicer1 gene in the adult forebrain, after induction of Dicer1 gene deletion, a progressive loss of a whole set of brain-specific miRNAs was observed.…”