Translational Control of Synaptic Plasticity and Memory - Biophysical Approaches to Translational Control of Gene Expression - page 285

Neurons are highly polarized cells with the cell body being separated by
hundreds of micrometers from their distal dendrites where synaptic contacts are
formed. One strategy to control the proteome at synapses is through protein synthe-
sis in the cell body and subsequent transport of newly synthesized components to
the distal locations. However, a substantial amount of data supports the idea that, in
neurons, many proteins are translated locally at synapses from preexisting mRNAs
(Bramham and Wells 2007 ). Indeed, dendrites of hippocampal neurons contain all
the necessary components to translate new proteins: numerous mRNAs are local-
ized in dendrites (Bramham and Wells 2007 ), ribosomes (Steward and Levy 1982 ) ,
translation initiation factors such as eIF4G, eIF4E, eIF4A, 4E-BP, as well as signal-
ing molecules of the MAPK-Mnk-eIF4E, mTOR, and CPEB1/gld2 pathway (Wu
et al. 1998 ; Tang et al. 2002 ; Asaki et al. 2003 ) . Moreover, LTP-inducing stimula-
tion causes ribosomes to move from dendritic shafts to spines with enlarged syn-
apses (Ostroff et al. 2002 ). Local translation at synaptic compartments enables fast
changes in the synaptic proteome in response to stimuli, and offers better spatial
control with a differential repertoire of proteins being translated at neighboring syn-
apses of the same neuron (Steward et al. 1998 ) . Remarkably, brain-derived neu-
rotrophic factor (BDNF) elicits L-LTP at Schaffer collateral-CA1 synapses in
hippocampus even when the cell bodies of presynaptic and postsynaptic neurons are
physically severed from the axons and dendrites respectively (Kang and Schuman
1996 ). L-LTP under these conditions was still impaired by protein synthesis inhibi-
tors, indicating that local translation in dendrites is required for L-LTP persistence.
When the protein synthesis inhibitor emetine was applied locally to the apical den-
drites of CA1 pyramidal cells in hippocampus, L-LTP was impaired at apical but not
at basal dendrites (Bradshaw et al. 2003 ), further supporting a key role of local pro-
tein synthesis for long-lasting plasticity. Other forms of synaptic plasticity, such as
L-LTP induced by subthreshold electrical stimulation in the presence of b -adrenergic
receptors agonist and LTD, are all dependent on local protein synthesis (Huber et al.
2000 ; Gelinas and Nguyen 2005 ) .
The rate of mRNA translation in eukaryotes is controlled by several signaling
pathways (Sonenberg and Hinnebusch 2009 ). Translation initiation is the rate-limiting
step under most circumstances and is a major target for regulation. In this chapter, we
review the current knowledge on the mechanisms controlling the rate of protein
synthesis in neurons in response to synaptic stimulation or behavioral training.

14.2 Translation in Eukaryotes

All nuclear transcribed eukaryotic mRNAs contain, at their 5¢ end, the structure
m7GpppN (where N is any nucleotide) termed the “cap,” which facilitates ribosome
recruitment to the mRNA. Ribosome recruitment requires a group of translation
initiation factors, termed eIF4 (eukaryotic initiation factor 4). An important member
of this group is eIF4F, which is a three subunit complex (Edery et al. 1983 ; Grifo
et al. 1983 ) composed of (1) eIF4A, an RNA helicase that is thought to unwind the