Healthcare and Medicine Reference
In-Depth Information
lated to produce antidromic action potentials in their
cell body, protein synthesis is not maintained (Hyson
and Rubel, 1989). Thus, the preservation of postsy-
naptic neuron metabolism, and presumably its sur-
vival, depend on the release of something from the
synaptic terminal.
Although we do not yet know what the trophic sub-
stance might be, there is some indication that neu-
rotrophins may be released by the afferent terminal
(Wang et al., 2002). The neurotransmitter itself may
also play a primary role in cell survival. Auditory
nerve fibers release glutamate at their synapse on NM
neurons, and this transmitter produces large excitatory
postsynaptic potentials. However, glutamate also acts
to limit the amount of calcium that enters NM neurons
by activating a metabotropic glutamate receptor
(mGluR). When auditory nerve fibers are stimulated in
the brain slice preparation, NM cytoplasmic calcium
levels remain low, but the addition of an mGluR antag-
onist during continued orthodromic stimulation
results in a rapid increase in calcium (Zirpel and Rubel,
1996). It is interesting that blockade of ionotropic glu-
tamate receptors in vivo can decrease normal cell
death in NM and block it entirely in nucleus laminaris
(Solum et al., 1997). Thus, excitatory afferents may
jeopardize survival through ionotropic glutamate
receptor activation but promote survival through acti-
vation of mGluRs.
Aprecipitous rise in cytoplasmic calcium may
dispose a cell toward death, but we have also learned
that it can elicit increased BDNF production and
increased survival, at least under culture conditions.
How can these two findings fit with one another?
One possibility is that the location of calcium entry
is crucial to gauging its effect (Sattler et al., 1998). In
cultured hippocampal neurons, activation of synaptic
glutamate receptors, called NMDA receptors, leads
to calcium entry and permits the cells to survive
an insult. However, when nonsynaptic NMDA recep-
tors are activated, again leading to calcium entry, the
neurons die. Therefore, the location at which calcium
enters the neuron appears to determine its effect on
neuron survival (Hardingham et al., 2002).
Although it seems as if the synaptic mechanisms
supporting neuron survival are quite different in the
chick cochlear nucleus and in hippocampal or cortical
cultures, there is one important similarity. In both
types of neurons, survival depends on CREB activa-
tion. In the hippocampal cultures, synaptic NMDA
receptor activity increases CREB phosphorylation,
leading to transcription of BDNF. Given the primary
role of CREB in mediating neurotrophin-dependent
survival (Figure 7.27), it would not be surprising if
synaptically mediated rises in phosphorylated CREB
A
Cochlea
removed
Cochlea
intact
Cochlea
removed
Cochlea
intact
B
100
80
60
40
20
0
-20
3
5
7
9
11
18
93
Normal
Age (postnatal days)
FIGURE 7.32 The survival of neurons in the gerbil cochlear
nucleus depends on afferent innervation from the cochlea only
through the first postnatal week. A. Cross section through the brain-
stem showing the ventral cochlear nucleus that was deafferented by
cochlea removal (left) and the cochlear nucleus that received normal
innervation (right). The cochlea was removed at P3. Shown below
are higher magnification images of a deafferented (left) and control
(right) cochlear nucleus from an animal in which the cochlea was
removed at P5. There are very few neurons remaining on the cochlea
removal side. B. The plot shows the percentage of nerve cells lost on
the cochlea removal side, as compared to the control side, for dif-
ferent ages of surgical removal. The number of neurons lost is 50%
or greater when the cochlea is removed by postnatal day 7.
However, there is no cell death when the cochlea is removed after
P9. (Adapted from Tierney et al., 1997).
neurons leads to a rapid decrease in protein synthesis
that is thought to be a condition preceding cell death
in this and many other neural systems. When the audi-
tory nerve is stimulated, NM neurons receive synapti-
cally evoked activity, and protein synthesis is
maintained. In contrast, when NM axons are stimu-
Search Pocayo ::




Custom Search