MicroRNA loss enhances learning and memory in mice.
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 (tamoxifen-inducible 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.
Molecular Biology of the Cell I, German Cancer Research Center, D-69120 Heidelberg, Germany. w.konopka@dkfz.de
Witold
W
Konopka
Anna
A
Kiryk
Martin
M
Novak
Marina
M
Herwerth
Jan Rodriguez
JR
Parkitna
Marcin
M
Wawrzyniak
Andreas
A
Kowarsch
Piotr
P
Michaluk
Joanna
J
Dzwonek
Tabea
T
Arnsperger
Grzegorz
G
Wilczynski
Matthias
M
Merkenschlager
Fabian J
FJ
Theis
Georg
G
Köhr
Leszek
L
Kaczmarek
Günther
G
Schütz
D000818:Animals; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D004558:Electric Stimulation / Q000379:methods; D004722:Endoribonucleases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D017353:Gene Deletion; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000235:genetics; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D009924:Organ Culture Techniques; D043244:Ribonuclease III; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure
D035683:MicroRNAs; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases