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Synapse Formation and Function
The formation of functional connections between
nerve cells distinguishes neural development from
that of all other tissues. This process begins with
axonal growth cones following a set of extracellular
cues to reach a precise location within a distant target
(see Chapters 5 and 6). When the growth cone finally
comes in contact with an appropriate postsynaptic cell,
a decision is made to stop growing and to differenti-
ate into a presynaptic terminal. Almost simultane-
ously, the target neuron begins to create a minute
specialization that will serve as the postsynaptic site.
In fact, both the growth cone and postsynaptic neuron
generate many of the components needed for neuro-
transmission well before innervation occurs, and the
formation of a functional contact can be remarkably
One general problem in studying synapses at any
age is that they are extremely small, often having a
contact length of less than 1 mm. This makes them
nearly impossible to see with a light microscope, and
one might wonder how they were discovered in the
first place. In fact, at the turn of the twentieth century,
one group of biologists believed that neuronal
processes fused with one another to produce long
fibers with a continuous protoplasm, called a syn-
cytium (Figure 8.1). Another group of scientists felt that
neurons remained separate, as had been shown for
other cell types, and that they must be in contact with
one another at the tips of their processes (Ramón y
Cajal, 1905). The great interest that was then focused
on the tips of neuronal processes led both to the dis-
covery of growth cones in very young tissue (see
Chapter 5) and to the first descriptions of presynaptic
terminals in older animals (Held, 1897). Charles Sher-
rington, winner of the 1932 Nobel Prize in Medicine,
realized that a separation between nerve cells would
allow for a new form of intercellular communication
(cf. chemical transmission), and he popularized the
term synapse (Sherrington, 1906).
The average mammalian neuron receives synapses
along its soma and dendrites, Some of these synapses
release glutamate, which excites the postsynaptic neuron;
others release GABA, which acts to inhibit the neuron;
and still others release various modulatory transmitters.
At a single glutamatergic synapse, there may be several
types of receptors; some will gate open ion channels while
others can activate a second messenger system. The
change in membrane potential brought about by this
synaptic transmission quickly recruits nearby ion chan-
nels (see Box: Maturation of Electrical Properties). In the
case of voltage-gated sodium channels, this leads to an
action potential.
This sanitized description of synaptic organization
highlights many of the challenges to a developing
nervous system. For example, the specific receptors
for GABA must be placed in the correct patch of post-
synaptic membrane. At the same time, each growth
cone must identify an appropriate patch of membrane
on which to differentiate. In the cortex, most gluta-
matergic synapses are located on postsynaptic spe-
cializations, called spines ; GABAergic synapses tend
to form on the cell body and proximal dendrite. A
tight little cluster of GABA A receptors on a dendritic
spine head would be of little use to the glutamate-
releasing terminals that are located there. There must
also be a mechanism to control the total number of
synapses that can form on any one neuron. That value
can vary tremendously, from over 10,000 for a cortical
pyramidal neuron to only a single excitatory synapse
on neurons of the medial nucleus of the trapezoid
To make some sense of this complexity, we will con-
sider separately how presynaptic terminals and postsy-
naptic specializations arise. Three general observations
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