Translational Control of Synaptic Plasticity and Memory - Biophysical Approaches to Translational Control of Gene Expression - page 291

reduced eIF2a phosphorylation, raising the possibility that the resulting increase in
general translation or the decrease in ATF4 translation might be important for LTP
and memory (Takei et al. 2001 ; Costa-Mattioli et al. 2007 ) . Indeed, genetic reduction
of eIF2a phosphorylation in eIF2a +/S51A knock-in mice or GCN2 (one of the major
eIF2a kinases) ablation had a strong impact on LTP and memory (Costa-Mattioli
et al. 2005, 2007 ). The threshold for L-LTP was lowered and learning and LTM was
enhanced in MWM, associative fear conditioning, and CTA tasks, while STM
remained intact. Accordingly, preventing activity-dependent eIF2a dephosphoryla-
tion with Sal003, an inhibitor of eIF2a phosphatase, impairs L-LTP and LTM.
Interestingly, in slices from ATF4 −/− mice, Sal003 was ineffective in reducing L-LTP,
indicating that impairment of L-LTP by Sal003 is mediated by ATF4.
Another study examined whether eIF2a's regulation of general translation or
gene-specific translation controls the conversion of STM to LTM (Jiang et al. 2010 ) .
When PKR (another eIF2a kinase)-mediated eIF2a phosphorylation was condi-
tionally increased in CA1 pyramidal cells in the hippocampus, L-LTP and memory
consolidation were impaired. The rate of de novo general translation was not
affected, whereas the translation of ATF4 was enhanced and CREB-dependent tran-
scription was suppressed. The authors concluded that the memory consolidation via
dephosphorylation of eIF2a depends more on gene-specific translation (decreased
ATF4 synthesis) and transcription (increased CREB-dependent transcription) than
on general translation. This conclusion was supported by the fact that low doses of
anisomycin, that reduced de novo general translation by ~70%, did not impair hip-
pocampal-dependent LTM.
It is still unclear how the activity of the eIF2a kinases are regulated by neuronal
activity. It was hypothesized that IMPACT, a GCN2 inhibitor that is present in the
brain, is rapidly upregulated by synaptic activity, leading to GCN2 inhibition (Costa-
Mattioli et al. 2009 ) .

14.4 Regulation of Translation by Polyadenylation and CPEB

Poly(A) binding protein (PABP) interacts with both the mRNA poly(A) tail and
eIF4G, leading to mRNA circularization and translational activation (Derry et al.
2006 ). The length of the poly(A) tail is controlled by the action of various poly(A)
polymerases and deadenylases. Regulation of mRNA poly(A) tail length by neu-
ronal activity emerges as an important mechanism in translational control of synap-
tic plasticity and memory. Cytoplasmic polyadenylation element (CPE)-binding
protein (CPEB) binds CPE sequences at proximal 3¢ UTR of mRNA and modulates
its poly(A) length. Several CPEB-associated proteins have been identified in
Xenopus oocytes: Gld2, a poly(A) polymerase, and PARN, a deadenylase and sym-
plekin that serves as a scaffold upon which regulatory factors are assembled (Kim
and Richter 2006 ). In unstimulated state the deadenylase activity of PARN prevents
poly(A) tail elongation. Activation of NMDA and metabotropic Glutamate receptors
(mGluRs) leads to CPEB phosphorylation by both Aurora A kinase and calcium/