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and synaptic plasticity. Upon neuronal activation with brain-derived neuro-
trophic factor (BDNF) or KCl, a number of signaling events, most notably
activation of the CaMKII (calcium/calmodulin-dependent kinase II)
phosphorylation cascade, result in local synaptic changes as well as in the
activation of transcription factors in the nucleus. Two of these transcription
factors, CREB and MeF2, have been shown to activate the transcription of
mir-132 and the cluster containing mir-134, respectively ( Fiore et al ., 2009 ;
Wayman et al ., 2008 ).
Increasedmir-132 levels uponCREB phosphorylation have two described
consequences. As mentioned above, mir-132 promotes dendritic growth and
branching, through its effect on the actin cytoskeleton. In addition, mir-132
downregulates MeCP2 (methyl CpG-binding protein 2), a broad tran-
scriptional regulator with a strong implication in the neurodevelopmental
disorder, Rett syndrome ( Klein et al ., 2007 ). Among MeCP2's targets is
BDNF itself; thus downregulation of MeCP2 by mir-132 results in a decrease
in BDNF transcription, suggesting that mir-132 plays a role in neuronal
homeostasis. Interestingly, CREB-mediated activation of mir-132 also occurs
in the suprachiasmatic nucleus, where it plays a role in modulation of the
circadian clock by light ( Cheng et al ., 2007 ), again illustrating how network
modules involving miRNAs can adopt different functions in different con-
texts. Notably, the miRNA bantam in Drosophila also plays a role in circadian
rhythm modulation ( Kadener et al ., 2009 ). The molecular oscillations that
underlie the circadian rhythms are sustained by interconnected feedforward
and feedback loops; miRNAs were likely an advantageous addition to these
networks to enhance not only their robustness but also their flexibility ( O'Neill
and Hastings, 2007 ).
Just as miRNA, biogenesis can be stimulated by neuronal activity, so can
miRNA catabolism ( Krol et al ., 2010 ). Filipowicz and colleagues found that
many miRNAs decay with much faster rates in neurons than in nonneur-
onal cells and that miRNA turnover in neurons is regulated by neuronal
activity. For example, blocking glutamate receptors in hippocampal neu-
rons slowed the decay of mir-124, -128, -134, and -138, while adding
glutamate made it faster ( Krol et al ., 2010 ). A rapid turnover of miRNAs
(given by fast rates of degradation but also fast rates of biogenesis) likely
allows neurons to adjust their repertoire of miRISC to the changing
environment, in order to respond accordingly by changing its morphology
or adjusting the strength of its synapses.
Finally, not only are the levels of miRNAs themselves affected by neuro-
nal activity but so is the composition of the RISC. Work in both Drosophila
olfactory interneurons ( Ashraf et al ., 2006 ) and in rat hippocampal neurons
( Banerjee et al ., 2009 ) has shown that upon neuronal activation, the DExD-
box protein Armitage/MOV10, which is found at the synapses, is degraded
via the ubiquitin-proteasome pathway. Reduction in the level of this key
component of the silencing complex results in the release of a number of
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