Translational Control of Synaptic Plasticity and Memory - Biophysical Approaches to Translational Control of Gene Expression - page 289

mTOR inhibition by rapamycin blocks L-LTP (Tang et al. 2002 ) , LTD (Hou and
Klann 2004 ), and memory consolidation in mammals in a number of behavioral tasks
(Shimizu et al. 2000 ; Dash et al. 2006 ; Bekinschtein et al. 2007 ; Schicknick et al.
2008 ; Stoica et al. 2011 ). A recent pharmocogenetic study showed that doses of
rapamycin, which are ineffective in blocking L-LTP and memory in wild-type mice,
inhibited L-LTP and LTM in mTOR heterozygous mice, thus providing the first
genetic evidence for the role of mTOR in synaptic plasticity and memory formation
(Stoica et al. 2011 ). Moreover, genetic mutants of the upstream and downstream com-
ponents to mTOR have been used to study the role of the mTOR pathway in LTM.
For example, TSC1 and TSC2 heterozygous mice show hyperactivation of the
mTOR pathway and alterations in synaptic plasticity and memory. TSC2 +/− mice
exhibit a lowered threshold for induction of L-LTP and impairment in hippocam-
pus-dependent LTM (Ehninger et al. 2008 ). Remarkably, brief rapamycin treatment
rescued the LTP and memory deficits, supporting the idea that the activity of mTOR
in the optimal range is essential for memory formation. TSC1 +/− mice similarly
demonstrate LTM deficits and impaired social behavior (Goorden et al. 2007 ) .
Conditional deletion of the rapamycin-binding protein FKBP12 in the forebrain
of mice (cKO) enhanced mTOR activity and increased S6K1 phosphorylation
(Hoeffer et al. 2008 ). L-LTP was enhanced relative to wild-type mice and was resis-
tant to rapamycin but was sensitive to anisomycin, a potent inhibitor of protein
synthesis. FKBP12 cKO mice exhibited enhanced contextual fear memory and
obsessive-compulsive behavior in several tasks, a phenotype frequently associated
with autism spectrum disorders (ASDs). Collectively, these results show that modu-
lation of mTOR pathway activity has a strong impact on L-LTP and memory and
can lead to ASD-associated behavior.
Intensive research has been conducted to elucidate the roles of the mTOR down-
stream targets, 4E-BPs and S6K1/2, in synaptic plasticity and memory formation.
Since no conditional transgenic lines for these proteins are available, the conclu-
sions derived from studies on general 4E-BPs and S6K1/2 knock-out mice should
be interpreted with caution, since long-term adaptation and feedback mechanisms
could be involved. Since 4E-BP2 is the major 4E-BP paralog in the brain, experi-
ments focused on 4E-BP2 KO mice. These mice displayed spatial learning deficits
and LTM impairment in several behavioral tasks (Banko et al. 2005, 2007 ) , but they
also exhibit a lowered threshold for the induction of L-LTP, similar to TSC2 +/− and
GCN2 −/− mice (Banko et al. 2005 ). Strong stimulation led to the obstruction of
L-LTP, which was suggested to result from translation hyperactivation in the absence
of 4E-BP2 (Banko and Klann 2008 ). In support of this theory, it was found that
although memory was impaired in most behavioral tasks, it was enhanced in an
insular cortex-dependent form of LTM—conditional taste aversion (CTA). In this
test, animals learn to associate an appetizing taste, such as saccharin, with gastric
distress induced by intraperitoneal injection of LiCl.
In accordance with the well-established role of 4E-BPs, a recent study demon-
strated the importance of eIF4F complex formation in memory consolidation
(Hoeffer et al. 2011 ). Prevention of eIF4E's interaction with eIF4G by the small
molecule 4EGI-1 impaired LTM, while STM remained intact. Interestingly, no