Translational Control of Synaptic Plasticity and Memory - Biophysical Approaches to Translational Control of Gene Expression - page 290

effect on reconsolidation was observed, suggesting that the requirement for the
eIF4E-eIF4G complex is different for these two memory processes.
The second major downstream targets of mTOR, S6K1 and S6K2, are also impli-
cated in memory formation. Intact L-LTP was measured in slices from S6K1 and
S6K2 KO mice. However, slices from S6K1-deficient mice displayed impaired pro-
tein synthesis-independent potentiation (E-LTP) (Antion et al. 2008b ) . Behavioral
studies revealed that S6K1-deficient mice express an early-onset contextual fear
memory deficit within 1 h of training, a deficit in conditioned taste aversion (CTA),
impaired Morris water maze (MWM) acquisition, and hypoactive exploratory
behavior. S6K2-deficient mice exhibit decreased contextual fear memory 7 days
after training (but not one) and a reduction in latent inhibition of CTA. Surprisingly,
mGluR-LTD was enhanced in S6K2 KO mice, whereas mGluR-LTD was intact in
S6K1 knockouts (Antion et al. 2008a ). Taken together, these results suggest that
mTOR signaling to S6K1/2 is not critical for expression of long-lasting synaptic
plasticity (L-LTP and LTD), findings that are difficult to explain in light of the
memory phenotype in S6K1 KO mice (Antion et al. 2008b ) . Redundancy with other
kinases, compensatory, or negative feedback mechanisms (for example activation of
insulin receptor substrate 1 [IRS-1] in the absence of S6Ks) could explain the lack
of an L-LTP phenotype. Although it is clear that S6K1/2 play a role in memory
formation, more studies using conditional knockout or knock-in mice are required
for more accurate examination of their functions. In contrast to the findings in mice,
long-term facilitation (LTF) in Aplysia was blocked by expression of dominant neg-
ative S6K (Weatherill et al. 2010 ) .
Both LTP and mGluR-LTD activate ERK and its downstream targets MAPK
signal-integrating kinase/MAPK-interacting kinase 1 and 2 (Mnk1/2), that in turn
phosphorylate eIF4E at Ser209 (Kelleher et al. 2004 ; Banko et al. 2006 ) . This is
consistent with the important role of ERK signaling in protein synthesis-dependent
synaptic plasticity and memory formation.

14.3.3 Signi fi cance of eIF2 a Phosphorylation

in Memory Formation

eIF2 a phosphorylation at Ser51 controls both the rate of general translation and
gene-speci fi c translation. eIF2 a phosphorylation precludes ternary complex forma-
tion and consequently impairs general translation. Paradoxically, translation of
mRNAs containing upstream open reading frames (uORFs) is stimulated (Harding
et al. 2000 ; Vattem and Wek 2004 ). Activating transcription factor 4 (ATF4) contains
two uORFs and its translation is stimulated upon eIF2a phosphorylation. ATF4, also
known as cAMP-responsive element binding protein-2 (CREB-2), represses cAMP
response element (CRE)-dependent transcription (Karpinski et al. 1992 ) that is
widely considered to be critical for establishing long-lasting synaptic potentiation
and memory (Bartsch et al. 1995 ; Pittenger et al. 2002 ) . Stimulation of hippocampal
slices with either BDNF, forskolin, tetanic stimulation, or behavioral training in rats