Healthcare and Medicine Reference
In-Depth Information
CHAPTER
7
Naturally Occurring Neuron Death
Nervous system differentiation is accompanied by
tremendous growth; neuron cell bodies and dendrites
expand, glial cells and myelin are added, blood vessels
arborize, and extracellular matrix is secreted. Even
after the period of neurogenesis has largely ended, the
human brain continues to increase in size from approx-
imately 400 grams at birth to 1400 grams in adulthood
(Dekaban and Sadowsky, 1978). Surprisingly, neuro-
genesis and this later period of growth overlap with
a tremendous loss of neurons and glia, both of which
die from “natural causes.” Depending on the brain
region, 20 to 80% of differentiated cells degenerate
during development (Oppenheim, 1991; Oppenheim
and Johnson, 2003).
Whether or not a neuron survives depends on many
factors (Figure 7.1). Soluble survival factors may be sup-
plied by the postsynaptic target, by neighboring nerve
and glial cells, or by the circulatory system. Neurons
also depend upon the synaptic contacts that they
receive, and deafferentation leads to atrophy or death.
These diverse signals are referred to as trophic factors
because one cell is nourished or sustained by another.
The first part of this chapter will describe the character-
istics of cell death in the developing nervous system.
Relatively little will be said of injury-evoked cell death.
We then discuss the trophic factors and intracellular
signals that regulate this process. Finally, we will learn
that electrical activity and synaptic transmission can
have an important influence on neuron survival.
the fate of a very large, easily recognized neuron found
at the surface of the skate spinal cord. He found that
these Rohon-Beard cells were born in the neural crest
and differentiated in the spinal cord, sending out
processes to the ectoderm before degenerating. At first,
it was difficult to accept the concept that neurons were
born, only to die a short time later. Although there had
been many reports of neuron death after their target
had been removed (see below), it was not clear that
postmitotic neurons were lost in any significant
number during normal development (Clarke and
Clarke, 1996).
We now understand that nerve cells participate
actively in their own demise through gene transcrip-
tion and protein synthesis, and this process is termed
apoptosis or programmed cell death (PCD). To the
trained eye, a dying neuron looks quite different from
a healthy one (Figure 7.2). The chromatin becomes very
condensed and aggregates at the nuclear membrane,
in a process called pyknosis. The plasma membrane
remains intact, but the neuron gradually shrinks
and small protuberances, called apoptotic bodies, are
pinched off from the cell body and are phagocytosed by
macrophages (Figure 7.3). PCD can also follow a second
course, called autophagic cell death , in which the cell
contents are sequestered in autophagic bodies and
destroyed by the cell's own lysosomes (Kinch et al.,
2003).
As the large, crescent-shaped aggregates of nuclear
material form, enzymes are activated that cleave the
DNA, producing fragments of about 180 base pairs.
Although this process is too small to see anatomically,
it is possible to stain the broken ends of DNA strands
with molecular markers. One technique, called TUNEL
(for T erminal transferase U TP N ick E nd L abeling),
employs an enzyme that attaches labeled nucleotides
to the exposed ends of the DNA fragments (Figure 7.4).
WHAT DOES NEURON DEATH
LOOK LIKE?
Naturally occurring neuron death was discovered
over a century ago by John Beard (1896), who followed
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