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.
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
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