Healthcare and Medicine Reference
mechanisms that accompany apoptosis in the absence
of injury or insult to the nervous system.
EARLY ELIMINATION OF
Although most of this chapter is devoted to the
signals that mediate survival and death in differenti-
ated neurons, there is a prominent period of apoptosis
during neurogenesis (Blaschke et al., 1996; Blaschke et
al., 1998; Rakic and Zecevic, 2000). During late embry-
onic development, cells within the proliferative zone
of the mouse cerebral cortex display heavy labeling
with a variant of the TUNEL technique, indicating a
high level of DNA fragmentation (Figure 7.5A). Elec-
tron micrographs reveal cells with dark condensed
nuclei and other anatomical hallmarks of apoptosis
(Figure 7.5B), and counts of pyknotic and TUNEL-
positive nuclei are remarkably similar.
The magnitude of cell death in the proliferative
zone appears to be similar to that observed in most
postmitotic populations. About 70% of the subventric-
ular zone cells in newborn rats can be double-labeled
with the TUNEL technique and BrdU, a marker of cell
proliferation. This suggests that cells die during the
early G1 phase of the mitotic cycle (Thomaidou et al.,
1997). Little is known about the signals that lead
proliferating cells to enter the apoptotic pathway.
However, evidence from cultured quail neural crest
cells indicate that cell-cell contact is involved. When
neural crest clusters were grown on a nonadhesive
substrate to prevent then from dispersing, the cells dis-
played a marked increase in TUNEL-labeling as com-
pared to dissociated crest cells that were permitted to
disperse (Maynard et al., 2000).
The presence of apoptosis in the proliferative zone
suggests that the total number of neurons in the brain
is regulated, in part, by the elimination of stem cells.
It also raises the interesting possibility that these
two stages of development—birth and death—share
certain molecular pathways, a concept that is dis-
cussed below (see Intracellular Signaling).
FIGURE 7.1 Five sources that influence neuron survival.
Neurons can receive survival signals from the cells that they inner-
vate (target-derived), from their synaptic inputs (afferent-derived),
from neighboring neuron cell bodies (paracrine), from distant
sources via the circulatory system (blood-born), and from nonneu-
ronal cells (glia-derived).
This approach is useful when studying cell death in a
large population of cells that has no clear boundaries,
such as an area of cerebral cortex. However, it should
not be considered a bullet-proof characterization of cell
death. Unlabeled cells may, in fact, enter a cell death
pathway in which chromatin breakdown and conden-
sation are not featured (Oppenheim et al., 2001).
The degenerative changes that follow a traumatic
injury are called necrosis , and they are usually distinct
from apoptosis. Following injury, the mitochondria
stop producing energy, and the neuron becomes
unable to regulate ionic content and hydrostatic pres-
sure. The neuron and its organelles begin to swell,
lysosomal enzymes become activated, and cytoplas-
mic components are broken down. Finally, the soma
bursts open (Figure 7.3). There is an important differ-
ence between a neuron that dies gracefully by budding
off neat little packages of membrane (apoptosis), com-
pared to one that dies violently by retching catabolic
enzymes on its neighbors (necrosis). Clearly, a grace-
ful death is unlikely to injure healthy neighboring
neurons, and serves as an efficient means to eliminate
these cells. For the most part, we will consider only the
HOW MANY DIFFERENTIATED
It might seem a straightforward matter to determine
how many neurons are being added or removed from
a population: Simply count the neurons in a young
animal, and subtract this number from an identical