Synapses exhibit many forms of plasticity that occur over a broad temporal range,
from seconds to minutes, to hours, days, or even years.
Many synapses exhibit long-lasting forms of plasticity that are manifested
by molecular or structural changes.
These changes may represent more permanent changes in brain function
and contribute to learning and memory.
One strategy for finding out how the nervous system is changed by a specific
learning task is to exploit the relative simplicity of the CNS of some invertebrates.
Eric Kandel and his colleagues at Columbia University used
the marine mollusk Aplysia californica to study the elemental forms
of behavioral and synaptic plasticity.
Aplysia exhibit several forms of behavioral plasticity.
For example, applying a tactile stimulus to the siphon of an Aplysia results
in withdrawal of the animal’s gill, but repeated siphon stimulation
causes the gill withdrawal to weaken.
The process that causes an animal to become less responsive to repeated
occurrences of a stimulus is called habituation.
The gill withdrawal response also exhibits a form of plasticity called sensitization.
In Aplysia that have habituated to siphon touching,
a strong electrical stimulus to the tail paired with a light touch of the siphon
elicits a strong gill withdrawal, as if the animal had not been habituated.
Sensitization allows an animal to generalize an aversive response elicited by
a noxious stimulus to a variety of other, non-noxious stimuli.
This graph shows the habituation of the gill withdrawal reflex following
repeated stimulation of the siphon.
In an Aplysia that receives a single stimulus to the tail,
the gill withdrawal reflex remains enhanced for about an hour.
With repeated pairing of tail and siphon stimuli, this behavior can be altered
for days or weeks, demonstrating a simple form of long-term memory.
Whereas four single tail shocks sensitize the gill withdrawal response
for a short time, repeated tail shocks for several days causes
prolonged sensitization of the gill withdrawal response.
The small number of neurons in the Aplysia nervous system makes it possible
to define the synaptic circuits involved in gill withdrawal
and to monitor the activity of individual neurons and synapses in these circuits.
For example, the cell bodies of many of the neurons involved in gill
withdrawal can be recognized by their size, shape,
and position within the abdominal ganglion.
Although hundreds of neurons are ultimately involved in producing
this simple behavior, the activities of only a few different types of neurons
can account for gill withdrawal during habituation and sensitization.
These critical neurons include sensory neurons that innervate the siphon,
motor neurons that innervate muscles in the gill,
and interneurons that receive inputs from a variety of sensory neurons.
Touching the siphon activates the sensory neurons, which form excitatory synapses
that release glutamate onto both the interneurons and the motor neurons.
By monitoring the electrical activity of the neurons, we can see the effect
that touching the siphon has on both of these postsynaptic targets.
Both habituation and sensitization appear to arise from plastic changes in
synaptic transmission in this circuit.
During habituation, transmission at the glutamatergic synapse
between the sensory and motor neurons is depressed.
This synaptic depression is thought to be responsible for the decreasing ability
of siphon stimuli to evoke gill contractions during habituation.
This depression is presynaptic and is due to a reduction in the number
of synaptic vesicles available for release.
As we will see, sensitization modifies the function of this circuit
by activating modulatory interneurons.
The tail shock that evokes sensitization activates sensory neurons
that innervate the tail.
These sensory neurons in turn excite modulatory interneurons that release serotonin
onto the presynaptic terminals of the sensory neurons of the siphon.
Serotonin enhances transmitter release from the siphon sensory neuron terminals,
leading to increased synaptic excitation of the motor neurons.
Now a light touch on the siphon can again elicit a strong gill withdrawal response.
Note that the modulation of the sensory neuron–motor neuron synapse lasts
approximately an hour, which is similar to the duration of the short-term sensitization
of gill withdrawal produced by applying a single shock to the tail.
Let us explore the biochemical mechanisms thought to be responsible for the
enhancement of glutamatergic transmission during short-term sensitization.
Serotonin released by the facilitatory interneurons binds to G-protein-coupled
serotonin receptors on the presynaptic terminals of the siphon sensory neurons,
activating the G-protein.
The activated G-protein dissociates from the receptor and binds to and activates
other signaling molecules such as the enzyme adenylyl cyclase.
This enzyme stimulates production of the second messenger cyclic AMP from ATP.
The cyclic AMP molecules bind to the regulatory subunits of protein kinase A (PKA),
liberating catalytic subunits of PKA that are then able to phosphorylate
several proteins, including potassium channels.
When a sensory neuron synapse is depolarized, calcium channels open,
and calcium ions enter the terminal.
Phosphorylation of potassium channels by PKA results in fewer open potassium channels,
thereby prolonging the duration of the depolarization
and increasing the influx of calcium.
The enhanced influx of calcium, in turn, results in more neurotransmitter being released.
In summary, short-term sensitization of gill withdrawal is mediated
by a signal transduction cascade that involves neurotransmitters,
second messengers, one or more protein kinases, and ion channels.
This cascade ultimately enhances synaptic transmission
between the sensory and motor neurons within the gill withdrawal circuit.
The same serotonin-induced enhancement of glutamate release that mediates short-term
sensitization is also thought to underlie long-term sensitization.
However, during long-term sensitization this circuitry is affected
for up to several weeks.
The prolonged duration of this form of plasticity is evidently due to
changes in gene expression and thus protein synthesis.
With repeated training (that is, additional tail shocks),
the serotonin-activated PKA involved in short-term sensitization now also
phosphorylates—and thereby activates—the transcriptional activator
cyclic AMP-response element binding protein (CREB).
CREB binding to the cyclic AMP responsive elements (CREs) in regulatory regions
of nuclear DNA increases the rate of transcription of downstream genes.
Although the changes in genes and gene products that follow CRE activation have been
difficult to sort out, several consequences of gene activation have been identified.
First, CREB stimulates the synthesis of an enzyme, ubiquitin hydroxylase.
CREB also activates the gene that encodes another protein called C/EBP.
Ubiquitin hydroxylase stimulates degradation of the regulatory subunit of PKA.
This causes a persistent increase in the amount of free catalytic subunit,
meaning that some PKA is persistently active
and no longer requires serotonin to be activated.
Like CREB, C/EBP is a transcription factor that
stimulates transcription of other, unknown genes.
The gene products result in the production of proteins that cause addition of
synaptic terminals, yielding a long-term increase in the number of synapses
between the sensory and the motor neurons.
Such structural increases are not seen following short-term sensitization
and may represent the ultimate cause of the long-lasting change in overall strength
of the relevant circuit connections that produce a long-lasting enhancement
in the gill withdrawal response.
It is thought that similar mechanisms may underlie the synaptic changes
that account for long-term memories in humans.