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  • 1
    Abstract: Dicer's essential role in development and neuronal survival has precluded studying its role in learning and memory. The study by Konopka et al. uses modern mouse genetics to address this question showing that loss of neuronal miRNA enhances learning and memory. Dicer is essential for the production of miRNA and Dicer loss of function leads to embryonic lethality. Using a number of Dicer conditional alleles, it has been demonstrated that miRNA is required for the survival of developing neurons (1-4). These important observations, however, have shed no light on the function of miRNA in mature adult neurons. Using a tamoxifen-inducible Cre transgene expressed in forebrain neurons, Konopka et al. disrupt miRNA biogenesis after neuronal maturation has occurred. Not surprisingly, at later timepoints after deletion of Dicer, significant neuronal loss in the hippocampus and cortex is observed. However, in a window of time 10-14 weeks after deletion, the authors observe improved performance in a variety of learning and memory-related tasks. Correlated with the improved performance the authors observed increases in post-tetanic potentiation and signs of increases in dendritic spine growth and mobility. Though not directly demonstrated by the result of miRNA depletion, the authors observed enhanced levels of brain-derived neurotrophic factor (BDNF), glutamate receptors, post-synaptic density protein 95 (PSD95), and matrix-metalloprotease 9 (MMP9). The increase in these proteins' levels may be the cause, or the consequence, of the improved memory of the Dicer mutant mice. Though loss of miRNAs leads to improved memory, this effect is only transient and eventually the mice show significant neurodegeneration. At this time it remains unclear whether the changes in protein levels that improve cognitive performance are the same proteins that eventually lead to neurodegeneration. References: 1 Schaefer et al. J Exp Med 2007, 204:1553-8 [PMID:17606634]. 2 Kim et al. Science 2007, 317:1220-4 [PMID:17761882]. 3 Cuellar et al. Proc Natl Acad Sci U S A 2008, 105:5614-9 [PMID:18385371]. 4 Davis et al. J Neurosci 2008, 28:4322-30 [PMID:18434510]. Competing interests: None declared
    Type of Publication: Miscellaneous publication
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  • 2
    Keywords: brain ; PROTEIN ; transcription ; synaptic plasticity ; DISRUPTION ; CELL-GROWTH ; FACTOR TIF-IA ; neurogenesis ; SEX-DIFFERENCES ; NUCLEOLAR STRESS
    Abstract: Decreased rRNA synthesis and nucleolar disruption, known as nucleolar stress, are primary signs of cellular stress associated with aging and neurodegenerative disorders. Silencing of rDNA occurs during early stages of Alzheimer's disease (AD) and may play a role in dementia. Moreover, aberrant regulation of the protein synthesis machinery is present in the brain of suicide victims and implicates the epigenetic modulation of rRNA. Recently, we developed unique mouse models characterized by nucleolar stress in neurons. We inhibited RNA polymerase I by genetic ablation of the basal transcription factor TIF-IA in adult hippocampal neurons. Nucleolar stress resulted in progressive neurodegeneration, although with a differential vulnerability within the CA1, CA3, and dentate gyrus (DG). Here, we investigate the consequences of nucleolar stress on learning and memory. The mutant mice show normal performance in the Morris water maze and in other behavioral tests, suggesting the activation of adaptive mechanisms. In fact, we observe a significantly enhanced learning and re-learning corresponding to the initial inhibition of rRNA transcription. This phenomenon is accompanied by aberrant synaptic plasticity. By the analysis of nucleolar function and integrity, we find that the synthesis of rRNA is later restored. Gene expression profiling shows that 36 transcripts are differentially expressed in comparison to the control group in absence of neurodegeneration. Additionally, we observe a significant enrichment of the putative serum response factor (SRF) binding sites in the promoters of the genes with changed expression, indicating potential adaptive mechanisms mediated by the mitogen-activated protein kinase pathway. In the DG a neurogenetic response might compensate the initial molecular deficits. These results underscore the role of nucleolar stress in neuronal homeostasis and open a new ground for therapeutic strategies aiming at preserving neuronal function.
    Type of Publication: Journal article published
    PubMed ID: 24273493
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  • 3
    Keywords: brain ; EXPRESSION ; CELL ; COMBINATION ; Germany ; VIVO ; SYSTEM ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; TRANSDUCTION ; INDUCTION ; RAT ; RATS ; TISSUES ; BIOLOGY ; TARGET ; hippocampus ; NERVOUS-SYSTEM ; VECTORS ; VECTOR ; PROMOTERS ; transgenic ; genetics ; MAMMALIAN-CELLS ; CENTRAL-NERVOUS-SYSTEM ; RAT-BRAIN ; LENTIVIRAL VECTOR ; EGFR ; HUNTINGTONS-DISEASE ; NEUROTROPHIC FACTOR ; USA ; Doxycycline ; lentiviral vectors ; TRANSGENIC RATS ; Genetic ; NEURONS IN-VITRO ; rtTA ; Tet system ; TIGHT CONTROL
    Abstract: Local and regulated expression of exogenous genes in the central nervous system is one of the major challenges of modern neuroscience. We have approached this issue by applying the inducible tetracycline system to regulate the expression of EGFP reporter gene in double transgenic rats. We have obtained a strong induction of EGFP only in male testes, which correlated with a high level of rtTA expression only in this organ. To overcome the problem of lack of rtTA protein in the transgenic rat brain, we have delivered this Tet system activator with lentiviral vectors into the dentate gyrus of hippocampus of transgenic EGFP rats. As a result, after systemic application of doxycycline we have obtained inducible, stable and restricted to the desired brain region expression of EGFR An advantage of this strategy is that the transgene is located in the same genetic milieu in every cell of the transgenic organism. This is crucial to obtain uniform expression of the regulated gene within the target brain structure. Combination of rat transgenesis and lentiviral vectors is a novel approach enabling precise spatiotemporal regulation of genes of interest strictly in the brain structure of choice or in other tissues. genesis 47:274-280, 2009. (C) 2009 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 19241392
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  • 4
    Abstract: J. Neurosci. 30, 14835-14842 (2010) Learning and memory in mice seem to be enhanced by the loss of small RNA molecules called microRNAs (miRNAs) in the brain. Witold Konopka at the German Cancer Research Center in Heidelberg and his colleagues deactivated the gene for Dicer, a key enzyme in miRNA synthesis, in forebrain neurons of adult mice. Twelve weeks later, the mice showed improved learning and memory in a behavioural test. This was mirrored by increased numbers of a type of dendritic spine in mutant neurons that is associated with learning. After 20 weeks, however, some of the neurons had degenerated, confirming the importance of microRNAs for neuronal survival.
    Type of Publication: Miscellaneous publication
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  • 5
    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 (tamoxifen-inducible CreERT2) under control of Camk2a gene regulatory elements. After induction of Dicer1 gene deletion in adult mouse forebrain, weobserved 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
    Type of Publication: Journal article published
    PubMed ID: 21048142
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