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A
B
Control
Increased NMJ activity
Segmental Nerve
(ether-a-go-go / Shaker mutant)
muscle 7
muscle 6
normal FasII expression
decreased FasII expression
C
Model
Activity stimulates CaMKII
DLG phosphorylation
Synapse growth
DLG
FasII
Ca
P
P
P
P
P
P
P
P
P
P
P
P
P
Ca
Ca
active
CaMKII
FIGURE 9.28 Activity-dependent synapse formation and cell adhesion molecules. A. In wild-type flies,
Muscles 6 and 7 receive about 180 boutons, and the expression of FasII is relatively high (left). B. In a double
mutant strain of flies ( ether-a-go-go /Shaker), synaptic activity is elevated at the neuromuscular synapse, and
FasII levels are lower. About 55% more boutonal endings are made on Muscles 6 and 7 in these flies (right).
C. One model to explain these results is that synaptic activity leads to calcium influx and activation of the
kinase, CaMKII (left). The active CaMKII phosphoyrylates a MAGUK protein that mediates clustering of
synaptic proteins, including FasII (middle). The phosphorylated DLG is not as restricted to the synaptic
complex, and FasII may no longer be located at the synapses, leading to less adhesion and sprouting of new
boutons. (Adapted from Budnik et al., 1990; Schuster et al., 1996; Koh et al., 1999)
and a 70% increase in boutonal endings on muscle 6/7.
The cAMP/PKA signal can lead to changes in protein
synthesis by phosphorylating specific activators or
repressors of transcription (see BOX: Remaining Flex-
ible). When dunce flies are engineered to carry a trans-
gene that maintains high levels of FasII expression, the
sprouting of motor terminals does not occur (Schuster
et al., 1996b). Thus, it appears that synaptic activity
may also influence the adhesion of pre- and postsy-
naptic cell through cAMP signaling.
opening an ion channel that is permeable to sodium,
potassium, and/or calcium. However, neurons typi-
cally express many different types of receptors, even
within a single synapse. Are there other synaptic
mechanisms involved besides ionotropic signaling?
This question has been approached by examining
synapse development in mice that are lacking specific
receptor subunits. One interesting possibility is that
glutamatergic transmission also activates metabo-
tropic glutamate receptors (mGluRs). Rather than
opening ion channels directly, mGluRs can activate
either of two different signaling pathways: phospho-
lipid metabolism or cAMP production.
One set of knockout mice that are deficient in a par-
ticular metabotropic glutamate receptor subunit,
mGluR1, exhibits significantly less synapse elimina-
tion at cerebellar Purkinje cells compared to controls.
Furthermore, normal synapse elimination can be
rescued in these mice by expressing the mGluR1a
transgene specifically in Purkinje cells (Kano et al.,
1997; Ichise et al., 2000). Furthermore, the metabo-
tropic glutamate receptor may well act through a
METABOTROPIC RECEPTORS
We have seen that mechanisms of synapse elimina-
tion are at least partially triggered by the primary
transmitter and receptor. Nicotinic AChRs are likely to
be involved in synapse elimination at the neuromus-
cular junction, and NMDARs appear to play an impor-
tant role in the elimination of central glutamatergic
synapses. Both of these signaling systems operate by
 
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