Translational Control of Synaptic Plasticity and Memory - Biophysical Approaches to Translational Control of Gene Expression - page 293

translational repression, and allows for its translation at synapses, which is critical
for olfactory learning (Ashraf et al. 2006 ) . Armitage's mammalian ortholog,
MOV10, is degraded in hippocampal neurons by the proteosome upon synaptic
activity, leading to mRNA unsilencing and the dendritic translation of both CaMKIIa
and the depalmitoylating enzyme lysophospholipase1 (Lypla1) (Banerjee et al.
2009 ). Recent reports illustrated the significance of miRNAs in synaptic plasticity
and memory in mammals. Forebrain-specific deletion of Dicer decreased brain-speci fi c
miRNAs and enhanced memory in several behavioral tasks (Konopka et al. 2010 ) .
Expression of plasticity-related genes, such as BDNF and Matrix metallopeptidase
9, was increased in KO mice. Transgenic mice overexpressing miRNA-132 exhibited
memory impairment in a novel object recognition task (Hansen et al. 2010 ) . Further
recent studies shed light on the functions of two other brain-specific miRNAs,
miRNA-134 has been shown to be involved in synaptic plasticity and memory
consolidation (Gao et al. 2010 ), while miRNA-128b regulates memory extinction
(Lin et al. 2011 ) .

14.6 Translational Regulation by Elongation Factors

While translational initiation is considered to be the rate-limiting step in translation
and the major target for regulation, translational regulation of the elongation pro-
cess has been implicated during distinct forms of synaptic plasticity and memory
formation. Eukaryotic elongation factor 2 (eEF2) regulates the elongation step of
translation and eEF2 phosphorylation by the specific eEF2 kinase (eEF2K) at Thr56
slows the rate of elongation and consequently decreases the rate of general transla-
tion. Remarkably, the translation of several mRNAs implicated in synaptic plastic-
ity is enhanced. Phosphorylation of eEF2 during mGluR-LTD inhibits general
translation, while specifically enhancing the translation of Arc/Arg3.1, CaMKIIa ,
and MAP1B mRNAs (Davidkova and Carroll 2007 ; Park et al. 2008 ) . It was hypoth-
esized that the stalling of elongation following eEF2 phosphorylation releases step-
limiting initiation factors (such as eIF4E), leading to the enhanced translation of
poorly translated mRNAs (Walden et al. 1981 ). Consistent with this hypothesis,
blocking elongation with low doses of cycloheximide effectively reduces general
translation, while enhancing the translation of Arc/Arg3.1 mRNAs (Park et al.
2008 ). eEF2 phosphorylation is regulated by neuronal activity. While it is induced
by mGluR-LTD, LTP in dentate gyrus and taste conditioning, it is reduced by fear
conditioning training (Belelovsky et al. 2005 ; Park et al. 2008 ; Im et al. 2009 ; Panja
et al. 2009 ) . eEF2 a KO mice demonstrate impaired mGluR-LTD and enhanced
L-LTP (Park et al. 2008 ) and overexpression of eEF2K in the hippocampus impairs
L-LTP and long-term fear memory (Im et al. 2009 ). These results indicate that the
phosphorylation status of eEF2 might have different impacts on synaptic depression
(mGluR-LTD) and synaptic potentiation (L-LTP).