120
Brain Development
high frequency, the postsynaptic mem-
brane potential is known to increase and
the situation can last from minutes to
several hours. This persistent increase in
the synaptic membrane potential is called
posttetanic potentiation
and in the
in vivo
context, the process is called l
ong-t
erm
f
acilitation (LTF) in
Aplysia
,whileinverte-
brates it is named l
ong-t
erm p
otentiation
(LTP). Morphologically, many buds and/or
branches termed
spines
are formed along
the postsynaptic dendrites. In addition,
the area of synaptic contact has been
demonstrated to become broader dur-
ing LTP. Molecularly, it is revealed in
the excitory synapses that components of
the postsynaptic ion channels are mod-
i±ed to facilitate the Ca
2
+
permeability
through the postsynaptic membrane. In-
creased amounts of Ca
2
+
then activate
the Ca
2
+
dependent kinase and further
modify ion channels to increase the Ca
2
+
permeability. Continuous Ca
2
+
accumu-
lations ±nally activate the PKA pathways
at the postsynapse, resulting in turning
on a set of gene transcriptions, such as
cell adhesion molecules, to strengthen the
synaptic junction. From the postsynaptic
membrane, signaling molecules such as
nitric oxide (NO) and neurotrophic factors,
such as BDNF (brain-derived neurotrophic
factor), are thought to be released and af-
fect transmitter release as well as survival
rates of the presynaptic neuron terminals.
Neurotrophic factors further play an im-
portant role in modulating components of
ion channels. Recently, the role of those
genes that are implicated in LTP forma-
tion have been eliminated by the gene
targeting method in mice (see Sect. 7), and
thesem
icemoreorlessshowedaberran
t
phenotype in the activity dependent gen-
eration of brain functional units during
development as well as during learning
and memory processes at adult stages, in-
dicating LTP might be a crucial element of
these intricate processes of the brain.
7
How can Molecular Functions in Complex
Tissues be Studied?
Many methods have been established to
determine molecular functions
in vivo
.
There are basically two methods to ex-
amine molecular functions:
loss-of-function
and
gain-of-function
studies. In the former,
a gene and/or its protein product of in-
terest is eliminated in the relevant tissue
and/or entire organism, and researchers
analyze the abnormalities to understand
its normal functions. In the latter, a gene
and/or its protein product is ectopically ex-
pressed in the tissue where the gene is not
expressed, and researchers examine the
acquired phenotypes of the tissue to know
its original functions. Here, I briefly out-
line emerging methodologies to clarify the
complex molecular functions in the brain.
7.1
Loss-of-function Studies
Applying materials that block generation
of a gene product and/or the function
o
fth
eg
en
ep
rodu
c
twou
ldb
eth
es
im
-
plest way in this criterion. For example,
several drugs/antagonists are known to
block functions of speci±c sets of ion
channels expressed by neurons, and these
reagents have been playing pivotal roles
in elucidating synaptic functions in the
nervous system. Designing
dominant neg-
ative molecules
could be another option
to inhibit the normal functions of en-
dogenous molecules. For instance, several
types of receptors such as Notch, BMP
receptors, FGF receptors, and so on are
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