Behavioral experiences can modulate neural networks through changes in synaptic morphology and number. In contrast, abnormal
morphogenesis of dendritic spines is associated with cognitive impairment, as in Fragile X syndrome. Dendritic or synaptic protein
Behavioral experiences can modulate the function of individual
synapses or entire neural networks through changes in synaptic
morphology and number (Bailey and Chen, 1983; Black et al.,
or activity can induce morphogenesis (or changes in shape or
motility) of postsynaptic spines, sites for excitatory synapses
phogenesis, in contrast, is associated with cognitive impairment,
as in Fragile X syndrome (FXS) and other disorders (Purpura,
1974; Hinton et al., 1991). Reactive spine morphogenesis likely
requires rapid availability of macromolecules, and dendritic or
synaptic protein synthesis could provide specificity and speed.
Although direct evidence tying local protein synthesis to spine
morphogenesis is scarce, we review the available indirect evi-
dence with an emphasis on locally translated proteins, including
the Fragile X mental retardation protein (FMRP), that have
known effects on synaptic morphology.
Markers of translation [polyribosomal aggregates (PRAs)]
have been observed near synapses during peak developmental
synaptogenesis (Steward and Falk, 1986), and local protein syn-
thesis is regulated by intrinsic and extrinsic signals (Schuman et
al., 2006). Greenough et al. (1985) found that PRAs were local-
ized to dendritic spines in the visual cortex of rats exposed to a
and size of synapses (Grossman et al., 2002). Induction of long-
term potentiation (LTP), an electrically induced change in syn-
tained PRAs were larger after stimulation, suggesting that local
translation was important for this morphogenesis.
of neurotransmitter receptor agonists. Weiler et al. (1997) used
synaptoneurosomes (synapses dissociated from cell bodies) to
show that stimulation of metabotropic glutamate receptors
lation of proteins (including FMRP). Vanderklish and Edelman
(2002) recently reported elongation of dendritic spines after
stimulation of mGluRs. Preincubation with a translation inhibi-
tor blocked elongation, but it remains unclear whether the pro-
tein synthesis required is specifically dendritic.
lish the importance of protein synthesis for memory, synaptic
morphogenesis, and cortical function (Agranoff and Klinger,
1964; Kleim et al., 2003). Failure to synthesize specific proteins
can profoundly affect synapse morphology. For example, pa-
tients with FXS (characterized by the absence of FMRP) exhibit
elevated spine density in the neocortex as adults and an abun-
dance of spines with morphologies commonly observed early in
development (Hinton et al., 1991; Irwin et al., 2001). This phe-
notype is also seen in the neocortex and hippocampus of adult
mice lacking FMRP (Fmr1 knock-out mice), suggesting a deficit
et al., 2006).
sible roles of local from somatic protein synthesis in specific
forms of synaptic plasticity (Pfeiffer and Huber, 2006). Studies
is both necessary and sufficient for establishment and mainte-
nance of LTP (Cracco et al., 2005; Vickers et al., 2005). Similarly,
2001) demonstrated that local protein synthesis is important for
synaptic potentiation after administration of the neurotrophin
BDNF and, more recently, have visualized dynamics of local
This work was supported by National Institutes of Health Grants MH35321, AG10154, and HD07333, by the
Correspondence should be addressed to Dr. William T. Greenough, Beckman Institute, University of Illinois at
TheJournalofNeuroscience,July5,2006 • 26(27):7151–7155 • 7151
translation associated with synaptic po-
tentiation. In the future, these techniques
and others in which protein synthesis is
restricted to the soma of intact neurons
(Miller et al., 2002; Bradshaw et al., 2003)
can delineate the necessity for local pro-
tein synthesis in spine morphogenesis.
Specific proteins and biochemical path-
of these pathways lead ultimately to actin
rearrangement in the spine cytoskeleton.
Rho GTPases such as Rac1, for example,
are upstream modulators of actin poly-
merization. Their activity is regulated by
environmental signals such as visual in-
put, and stimulation of these Rho GTPase
pathways affects spine morphology and
stability (Sin et al., 2002; Tashiro and
Yuste, 2004). Proteins that are important
for spine formation and remodeling and
that are locally translated can be grouped
into two broad functional categories: (1)
mation and remodeling and (2) “plastic
structural elements” that integrate struc-
turally into the synapse, thus influencing
synaptic physiology and potentially alter-
Although evidence directly linking local
synthesis of specific proteins to spine
changes is sparse, proteins from both of
phogenesis (Fig. 1).
proteins or signaling cascades involved in morphogenesis. For
example, local translation of kinases or phosphatases could rap-
idly shift the equilibrium among pathways operating within the
spine. Synthesis of RNA-binding proteins would have longer-
term effects (Wells, 2006).
FMRP. The Fmr1 mRNA is found in neuronal somata, den-
drites, and spines. Activation of mGluRs localizes Fmr1 to den-
drites and initiates translation of FMRP in synaptoneurosomes
(Weiler et al., 1997; Antar et al., 2004). Activity-induced transla-
tion of FMRP could affect spine morphology via interactions
with its protein binding partners, including cytoplasmic FMRP
interacting protein 1 (CYFIP1) (Schenck et al., 2003). In Dro-
may also regulate other members of this actin-polymerization
as reduced head morphing and reduced spine stability (Tashiro
and Yuste, 2004).
In addition to being synthesized at synapses, FMRP binds
mRNA and ribosomes and seems to regulate mRNA transport
and synaptic protein synthesis (Weiler et al., 1997; Khandjian et
al., 2004). Weiler et al. (2004) found that stimulating mGluRs in
as Map1B mRNA, shown recently to colocalize with FMRP near
tubules, and microtubule stability seems to be increased in Fmr1
knock-out mice (Lu et al., 2004). Whereas these observations
indicate that FMRP is important for initiating translation at syn-
apses, FMRP may also inhibit constitutive protein synthesis else-
where in the cell (Laggerbauer et al., 2001; Li et al., 2001). To-
gether, these findings support a dual role for FMRP: delivery of
activity-dependent translation (Davidovic et al., 2005; Weiler,
mal spine morphology in FXS: (1) loss of protein–protein inter-
actions leading to disruption of morphogenesis pathways; (2)
dysregulated local synthesis of proteins important for morpho-
which could be critical for spine morphogenesis. These cargoes
(CaMKII) (discussed below), calbindin, the ?-glucocorticoid re-
ceptor, and cadherins (for more complete lists, see Sung et al.,
port and translation of FMRP cargoes may underlie many other
symptoms of FXS, as well (Markham et al., 2006).
CaMKII. CaMKII makes up a substantial proportion of the
postsynaptic density (PSD) and may function both as a regula-
7152 • J.Neurosci.,July5,2006 • 26(27):7151–7155Grossmanetal.•FragileXSyndrome
tory kinase and a scaffolding molecule for recruiting synaptic
proteins (Merrill et al., 2005). Local protein synthesis appears to
play a significant role in the regulation of dendritic CaMKII; its
mRNA is observed throughout apical dendrites of hippocampal
neurons, and mice missing dendritic targeting regions of
?-CaMKII mRNA have reduced levels of the protein in their
PSDs (Martone et al., 1996; Miller et al., 2002). The dynamics of
(Zalfa et al., 2003). Introducing phosphorylated CaMKII causes
immediate formation of long, thin filopodia and shorter den-
dritic spines; in contrast, preventing CaMKII phosphorylation
dain et al., 2003). In mice in which CaMKII is restricted from
dendrites, late-phase LTP and spatial memory are impaired, as
(Miller et al., 2002).
The proposed roles of CaMKII in spine morphogenesis are
threefold. (1) It phosphorylates signaling proteins, potentially
activating or repressing morphogenesis pathways. For example,
CaMKII phosphorylates SynGAP (synaptic GTPase-activating
way (Song et al., 2004). (2) CaMKII acts as a regulator of protein
translation through activation of cytoplasmic polyadenylation
element-binding protein (CPEB) (Atkins et al., 2004) and could
by accumulating at the PSD in response to neuronal stimulation
(Otmakhov et al., 2004), and by binding nearby synaptic pro-
are important for spine morphogenesis, may be recruited to syn-
apses by CaMKII (Zhou et al., 2004; Robison et al., 2005). Addi-
tional studies restricting CaMKII to the somata (Miller et al.,
2002) should examine spine morphology to determine whether
Plastic structural elements
Local synthesis of synaptic structural elements used by rapidly
developing or remodeling spines can replenish pools of raw ma-
change, or plasticity. For example, mRNA for the cytoskeletal
protein ?-actin is localized to dendrites in an activity-dependent
manner (Tiruchinapalli et al., 2003). Upregulation of ?-actin
mRNA stimulates the formation of dendritic filopodia, whereas
exclusion of ?-actin mRNA from dendrites disrupts the produc-
of actin filaments provides a dynamic scaffold for localization of
additional kinases and receptors (Ouyang et al., 2005), poten-
tially affecting postsynaptic responses and the capacity of the
spine to exhibit future morphogenesis. The concept of plastic
and may enable “synapses to integrate a response across tempo-
rally spaced episodes of synaptic activity” (Abraham and Tate,
PSD-95. PSD-95 is a locally synthesized scaffolding molecule,
the expression levels of which increase after stimulation of
mGluRs (Todd et al., 2003; Lee et al., 2005). Overexpression of
PSD-95 in cultured hippocampal neurons leads to synapse mat-
uration, clustering of glutamate receptors, and increased spine
density and size (El-Husseini et al., 2000). PSD-95 can also bind
and recruit to the PSD essential synaptic components, many of
which independently affect spine shape (e.g., NMDA receptors,
Homer, and others) (Kim and Sheng, 2004). Furthermore,
PSD-95 binds and targets to synapses kalirin-7, a regulator of
Rac1 signaling and spine morphogenesis (Penzes et al., 2001).
Finally, the mGluR-induced increase in PSD-95 appears to re-
genesis and may affect spine responsiveness to future signals.
SHANK and Homer. SHANKs are scaffolding elements that
mRNAs for SHANK1 and SHANK3 are localized to dendrites,
and SHANK has dramatic effects on spine morphogenesis, in-
ducing development of spines on non-spiny neurons (Bockers et
al., 2004; Roussignol et al., 2005). It interacts with actin-
associated proteins such as cortactin and appears to assemble
NMDA receptors and mGluRs at spines (Boeckers et al., 2002).
SHANK may exert some of its synaptic effects by binding the
ing synaptic components such as IP3receptors, PSD-95, and
can cluster mGluRs at plasma membranes and can interact with
Rho GTPase pathways (Shiraishi et al., 1999; Kammermeier,
2006), thus potentially affecting postsynaptic responses to neu-
rotransmitter signals. Together, the SHANK–Homer2 complex
increases the density of mushroom and multi-synapse spines
(Sala et al., 2001). In mice lacking FMRP, phosphorylation of
Homer protein is impaired, as is its association with mGluRs;
lower levels of PSD-associated mGluRs in Fmr1 knock-out mice
suggest that Homer dysregulation contributes to the spine phe-
notype of FXS (Giuffrida et al., 2005).
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