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The cellular mechanisms responsible for changes of
synaptic strength have been explored most thoroughly in
adult animals because of their importance in learning and
memory. Synaptic plasticity has been studied in a wide
variety of neuronal systems, from molluscan ganglia to
mammalian cerebral cortex, yet the catalog of cellular,
molecular, and genetic mechanisms has grown steadily.
This is probably good news for those interested in devel-
opmental plasticity because many of the ideas and tech-
niques have been imported successfully.
The very first inquiries into synaptic mechanisms of
plasticity demonstrated that synaptic transmission could
be enhanced for about one minute following a period
of intense stimulation. Recordings from muscle cells
revealed that post-tetanic facilitation occurred because
more neurotransmitter was released from the presynaptic
terminal (Larrabee and Bronk, 1947; Lloyd, 1949). For the
most part, contemporary studies continue to rely on intra-
cellular recordings, usually in conjunction with a drove of
“magic bullets” that are designed to block the function of
a specific molecule. A relatively new approach makes use
of genetic manipulations in the fruit fly and the mouse to
provide an important experimental link between gene
products, synaptic function, and behavior.
The modern era of cellular research began in the 1960s
when the classical conditioning paradigm of paired
stimuli was applied directly to a molluscan nervous
system. In an intact sea slug, Aplysia , it is possible to
enhance a touch-evoked withdrawal of the siphon when
the tactile stimulus is paired with an electric shock during
a training period. To study the neural basis of this sensiti-
zation, afferent-evoked EPSPs were recorded intracellu-
larly from an identified neuron in the abdominal ganglion,
and stimuli were delivered to both afferent pathways
simultaneously. Following paired stimulation, one of the
synapses produced much larger EPSPs, and this effect
lasted for up to 40 minutes (Kandel and Tauc, 1965b). The
increase was termed heterosynaptic facilitation because
synaptic transmission at one set of synapses modified the
functional status of a second, independent set.
One of the most compelling examples of synaptic plas-
ticity, called long-term potentiation (LTP), was first identified
in the early 1970s. By recording extracellularly from the hip-
pocampus of anesthetized rabbits, it was found that a brief,
high-frequency stimulus to the afferent pathway resulted
in an enhancement of the evoked potential that lasted for
hours to days (Bliss and Lømo, 1973). Over the next few
years, intracellular recordings from mammalian brain slice
preparations demonstrated that the size of EPSPs also
increased following tetanic afferent stimulation. LTP is now
thought to be one mechanism by which synapses store
information because humans with hippocampal lesions
display memory deficits, and a drug that blocks LTP in vitro
is also able to impair spatial learning in rodents.
The discovery of a cellular analog of learning has raised
many questions about the cellular mechanisms and the
molecular pathways involved. Recent studies have indi-
cated that two types of changes can occur at a potentiated
synapse: increased transmitter release and enhanced postsy-
naptic response. One likely scenario for LTP in the hip-
pocampus has glutamatergic transmission and postsynaptic
depolarization combining to activate NMDARs, allowing
calcium to flood the postsynaptic cell. NMDA receptor-
dependent learning has also been demonstrated both in
Aplysia (Murphy and Glanzman, 1999) and Drosophila (Xia et
al., 2005). Thus, this molecular mechanism may be an evolu-
tionarily conserved form of synaptic plasticity.
The influx of calcium activates one or more kinases
which, in turn, phosphorylate proteins at the synapse.
Although it is still not clear how many proteins are mod-
ified, there is evidence that functional glutamate receptors
are added to the membrane, thus enhancing the post-
synaptic response. A very simple form of learning in
Aplysia , long-term facilitation of transmitter release, illus-
trates another important molecular pathway. An increase
in presynaptic cAMP leads to the activation of a cAMP-
dependent protein kinase (PKA). Once activated, the PKA
subunit travels to the nucleus where it phosphorylates a
transcription factor. The facilitated transmitter release
involves new gene expression and protein synthesis
(Kaang et al., 1993).
The cAMP signaling pathway seems to be a primary
bridge to the formation of long-term memories in fruit flies
and mice. There are two cAMP-dependent transcription
factors (CREB), one that activates gene expression and a
second that represses it. Thus, when transgenic flies are
bred to express the activator, they remember an odor with
much less training. However, flies that express the repres-
sor are unable to store long-term olfactory memories (Yin
et al., 1994, 1995). The many experimental studies on CREB
(in Aplysia , fly, mouse and rat) established that the nucleus
was involved in long-term memory formation. This fact
presented an interesting question: How are these nuclear
signals—common to all synapses of a given neuron—give
rise to synapse-specific structural and functional modifi-
cations? The emerging answer seems to involve the
“pumilio/staufen” pathway (Dubnau et al., 2003), which
is involved in subcellular transport of mRNA and the local
control of protein translation. The genetic approach to
learning and memory clearly holds the promise of uniting
cellular and behavioral findings, and it is likely that studies
of developmental plasticity will profit as well.
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