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Reticular Theory
Neuron Theory
astrocyte
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ECM
Soma
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FIGURE 8.1 Reticular versus neuron theory. Over a century ago, the nervous sytem was thought to be a
syncytium (left) of cells that were joined together by their processes. This arrangement would permit elec-
trical activity to travel through the syncytium (arrows) in either direction upon stimulation. As evidence
mounted that neurons were separate cells (right), it was recognized that a chemical synapse (inset) would
permit electrical activity to travel in only one direction. ECM, extracellular matrix; PSD, postsynaptic density.
Electron microscopy permitted neuroscientists to see
the complex structure of synaptic contacts for the first
time. Intracellular recordings allowed one to observe
their electrical behavior (Palade and Palay, 1954; Fatt
and Katz, 1951). Together, these techniques established
the benchmarks by which we determine whether two
nerve cells are, in fact, connected to one another.
For the sake of simplicity, we begin with an ana-
tomical description of synaptogenesis; the molecular
and physiological transformations that accompany
them are considered below. At the ultrastructural level,
there are three clear signs of a synaptic specialization:
small vesicles accumulate at the presynaptic mem-
brane, a narrow cleft filled with extracellular matrix is
found between pre- and postsynaptic membranes, and
the postsynaptic membrane appears thickened owing
to the accumulation of membrane associated proteins
and cytoskeletal elements, called the postsynaptic
density (PSD). In contrast, newly formed synapses
have few, if any, vesicles in the presynaptic terminal
profile (Figure 8.2). In the rodent cortex, the average
number of vesicles found in a synaptic profile increases
almost threefold during the first postnatal month
(Dyson and Jones, 1980). A second characteristic of newly
formed synapses is the close apposition of pre- and
postsynaptic membranes, referred to as a tight junction
(Figures 8.2 and 8.3). Finally, the postsynaptic mem-
brane does not yet display a PSD. Therefore, newly
formed synapses do not display any of the adult ana-
tomical features, making them almost unrecognizable.
Even the highest power electron microscope cannot
detect the onset of synaptogenesis between a growth
cone and postsynaptic cell (Vaughn, 1989). There is
simply not much to be seen. More importantly, the
morphology cannot tell us how the synapse is
working. To get around these problems, many scien-
tists have turned to the tissue culture technique where
it is possible to watch cells come into contact with one
another, and monitor synapse morphology and func-
tion from moment to moment. The earliest tissue
culture studies demonstrated that mature synapses
could form in isolated pieces of neural tissue, but
the temporal resolution was comparable to the best in
vivo studies. When it became possible to observe
the growth cone approaching a postsynaptic target
neuron, then observations were first made close to the
onset of synaptogenesis.
One of the first in vitro systems consisted of a piece of
fetal rat spinal cord plated next to dissociated neurons
from the superior cervical ganglion, a target of auto-
nomic motor neurons (Rees et al., 1976). Within the first
several hours of contact, there are only subtle changes
in morphology to indicate that synapse formation is
underway (Figure 8.3). Of course, this is precisely why
in vivo observations could not detect the very onset of
synapse formation. At first, the growth cone loses its
filopodia and forms a punctate contact that is unusually
close to the postsynaptic cell membrane (about 7 nm,
less than the diameter of a hemoglobin molecule). This
suggests that an adhesive interaction may be involved
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