Translational Control of Synaptic Plasticity and Memory - Biophysical Approaches to Translational Control of Gene Expression - page 296

prevalence of macrocephaly amongst children with ASD (Courchesne 2004 ) .
Knockout mouse models of PTEN display deficits in social interaction, social learn-
ing, and behavioral abnormalities in response to sensory stimuli, anxiety, and learn-
ing (Kwon et al. 2006 ). These mice also have abnormal dendritic and axonal growth
and synapse numbers. Similarly, TSC2 +/− mice display memory deficits (Ehninger
et al. 2008 ) and an enlargement of neuronal somata and dendritic spines (Tavazoie
et al. 2005 ). Activation of the mTOR pathway leads to growth and branching of
dendrites, whereas rapamycin treatment or the overexpression of 4E-BP1 blocks the
effect in cultured neurons (Jaworski et al. 2005 ). Rapamycin prevents and reverses
neuronal hypertrophy, resulting in the amelioration of a subset of PTEN-associated
abnormal behaviors, thus providing strong evidence that the mTORC1 pathway
downstream of PTEN is critical for this complex phenotype (Zhou et al. 2009 ) .
Interestingly, brief treatment with rapamycin in adult TSC2 +/− mice rescues not only
the synaptic plasticity deficit, but also the behavioral deficits in this mouse model.
Finally, FKBP12 conditional knockout (cKO) mice display autistic/obsessive-
compulsive-like perseveration (Hoeffer et al. 2008 ) .
A link between eIF4E and autism was recently reported. In a boy with classic
autism a de novo chromosome translocation between 4q and 5q was mapped to the
eIF4E gene (Neves-Pereira et al. 2009 ). Strikingly, the screening of 120 autism
families for mutations revealed two unrelated families in which both autistic sib-
lings and one of the parents harbored the same single nucleotide insertion at posi-
tion 25 in the basal element of the eIF4E promoter (Neves-Pereira et al. 2009 ) . This
mutation results in both increased levels of eIF4E mRNA and protein amounts.
The implication of eIF4E in ASDs is further strengthened by recent findings that
CYFIP1, an eIF4E-binding protein, is also associated with ASDs. CYFIP1 is a bind-
ing partner of FMRP (Schenck et al. 2001, 2003 ) and directly binds to eIF4E to repress
neuronal translation in an activity-dependent manner (Napoli et al. 2008 ) . Thus,
CYFIP1 represses translation by directly binding to eIF4E and preventing the forma-
tion of the eIF4F complex, in a manner similar to the 4EBPs. Interestingly, CYFIP1
has been proposed as a risk gene for autism in ASDs, Prader Willie syndrome (PWS),
and Angelman syndrome patients through microduplication or microdeletion
(Doornbos et al. 2009 ) of the 15q11.2 chromosomal region or deletions in the 15q.11-
q13 (Sahoo et al. 2006 ). Furthermore, CYFIP1 mRNA levels are reduced in both
PWS and FXS patients (Nowicki et al. 2007 ). This shows that eIF4F complex forma-
tion, which regulates translation initiation, can be dysregulated in ASDs.
A common feature of neurodegenerative diseases (such as Parkinson's or
Alzheimer's) is the accumulation of aberrant or misfolded proteins that eventually
aggregate to form inclusion bodies. This pathological state can be attributed to dys-
regulated translational control. In Parkinson's disease (PD), resting tremor, slow-
ness of movement, rigidity, and postural instability are linked to the cell-death of
dopaminergic neurons in the substantia nigra. In Drosophila models of PD, it has
been shown that rapamycin can have beneficial effects (preventing loss of neurons,
flight muscle degeneration, climbing deficits, and mitochondrial alterations) and
that this effect depends on 4E-BP activation but not autophagy induction (Tain et al.
2009 ). In Alzheimer's disease (AD), profound memory loss and cognitive dysfunction