Translational Control of Synaptic Plasticity and Memory - Biophysical Approaches to Translational Control of Gene Expression - page 297

have been linked to increased mTOR activity and signaling in cellular and animal
models (Caccamo et al. 2010, 2011 ) . In these AD models, A b (beta-amyloid) accu-
mulations induce mTOR hyperactivation and rapamycin treatment decreases Ab
depositions and rescues cognitive deficits. Interestingly, phosphorylation of eIF2a
has been shown to increase the translation of BACE1 (beta-site APP cleaving
enzyme-1) (O'Connor et al. 2008 ). BACE1 is elevated in AD and is the rate limiting
enzyme for Ab production. Accordingly, phospho-PKR and phospho-eIF2a immu-
noreactivity is higher in AD-affected brains compared to age-matched controls
(Chang et al. 2002 ) .

14.9 Conclusions

Neuronal activity induces mild increase of general translation, but the translation of
certain mRNAs which are critical for synaptic plasticity and memory is significantly
stimulated. Although inhibition of mTOR signaling by rapamycin reduces total pro-
tein synthesis by only ~12%, in contrast to the 50-90% reduction by the general
protein synthesis inhibitor anisomycin (Beretta et al. 1996 ; Parsons et al. 2006 ) ,
strikingly, rapamycin impairs memory as strongly as anisomycin. This is explained
by the fact that mTOR stimulates the translation of a subset of mRNAs which are
critical for memory formation. However, the identity of these mRNAs remains
unknown. Similarly, regulation of specific mRNAs by eIF2a dephosphorylation, in
contrast to the enhancement of global translation, appears to be critical for synaptic
plasticity and memory formation (Costa-Mattioli et al. 2007 ; Jiang et al. 2010 ) .
Translational control at the 3¢ UTR by regulation of poly(A) tail length is emerging
as an important mechanism for synaptic plasticity and ongoing in vivo research will
shed new light on the role of this important mode of translational regulation in
memory formation. Most importantly, the aberrant translational control in ASD
mouse models and the high percentage of single-gene mutations in the upstream
components of the mTOR pathway (TSC1/TSC2 and PTEN) in ASD patients
prompted intensive research to identify the mRNAs whose abnormal translation
leads to an autistic phenotype.

Acknowledgments We thank Valerie Henderson and Ruifeng Cao for critical reading of the

chapter.

References

Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R (1997) Genetic demon-
stration of a role for PKA in the late phase of LTP and in hippocampus-based long-term mem-
ory. Cell 88(5):615-626
Alarcon JM, Hodgman R, Theis M, Huang YS, Kandel ER, Richter JD (2004) Selective modula-
tion of some forms of schaffer collateral-CA1 synaptic plasticity in mice with a disruption of
the CPEB-1 gene. Learn Mem 11(3):318-327