Translational Control of Synaptic Plasticity and Memory - Biophysical Approaches to Translational Control of Gene Expression - page 292

calmodulin-dependent protein kinase II (CaMKII), triggering poly(A) tail elongation
of CPE-containing mRNAs (probably by dissociation of PARN from the complex
and Gld2 activation) and their enhanced translation (Huang et al. 2002 ; Atkins et al.
2004 ; Shin et al. 2004 ; Kim and Richter 2006 ). In neurons, CPEB is present in post-
synaptic densities (PSD) in hippocampus (Wu et al. 1998 ) . Importantly, several
molecules with well established functions in learning and memory, such as CaMKIIa
and tissue plasminogen activator (TPA), contain CPE sequences in their 3¢ UTRs
and their mRNA poly(A) tails are elongated in response to stimulation (Wu et al.
1998 ; Shin et al. 2004 ). Visual experience induces elongation of CaMKIIa mRNA
poly(A) tail and its subsequent translation in the visual cortex (Wu et al. 1998 ) . The
significance of CPEB for protein synthesis-dependent synaptic plasticity and mem-
ory was investigated in CPEB-1 KO mice. Theta burst-induced L-LTP was impaired
in slices from KO mice, while four trains of high frequency stimulation elicited
normal L-LTP, suggesting stimulus specificity in engaging the CPEB pathway
(Alarcon et al. 2004 ). Behavioral studies revealed normal hippocampus-dependent
learning and memory; however, the extinction of these memories was impaired
(Berger-Sweeney et al. 2006 ). Though extinction is protein synthesis-dependent,
the underlying mechanisms are somewhat different from those of memory consoli-
dation (Herry et al. 2010 ). Another study found that CPEB controls the translation
of the transcription factor c-jun, which in turn regulates the expression of a growth
hormone that is also implicated in synaptic plasticity (Zearfoss et al. 2008 ) .
In Aplysia , CPEB is translated locally at the activated synapses and is required
for persistence of long-term synaptic facilitation. Interestingly, Aplysia CPEB
(ApCPEB) exhibits prion-like properties, forming a self-sustaining multimer (Si
et al. 2003a, b ). Formation of CPEB multimers is enhanced by the neurotransmitter
serotonin, and is believed to contribute to persistence of synaptic facilitation over
long periods of time (Miniaci et al. 2008 ; Si et al. 2010 ) .

14.5 Role of miRNAs in Synaptic Plasticity and Memory

MicroRNAs (miRNAs) are small (~21 nucleotide) noncoding RNAs that bind to
the 3¢ UTR of target mRNAs and suppress their expression by mechanisms that are
not fully elucidated. Many miRNAs are present in the brain (Kosik 2006 ) and the
expression of some miRNAs is transcriptionally regulated by neuronal activity
(Khudayberdiev et al. 2009 ; Nudelman et al. 2010 ; Wibrand et al. 2010 ) . Components
involved in the regulation of miRNA functions including Dicer, Argonaute, Fragile-X
mental retardation protein (FMRP), P-bodies along with numerous miRNAs are
present in dendrites, suggesting their possible role in the regulation of protein syn-
thesis-dependent plasticity and memory (Lugli et al. 2005 ; Kye et al. 2007 ) . For
example, in Aplysia , miR-124 has been shown to constrain LTF and was rapidly
downregulated by serotonin, a neurotransmitter critical for LTF (Rajasethupathy
et al. 2009 ) . In Drosophila , proteasome-dependent degradation of Armitage, a heli-
case required for miRNA-mediated gene repression, relieves CaMKII mRNA from