Healthcare and Medicine Reference
In-Depth Information
APPEARANCE OF
SYNAPTIC INHIBITION
etan and van den Pol, 1995). As the cultures mature,
bicuculline increases calcium, presumably by allowing
excitatory synaptic acitivity to have a greater depolar-
izing influence (Figure 8.33B). Therefore, inhibitory
synapses may provide a qualitatively different input
to postsynaptic neurons during development.
Inhibitory postsynaptic potentials gradually
become hyperpolarizing during development, as has
been demonstrated in the spinal cord, brainstem, hip-
pocampus, and cortex (Kandler and Friauf, 1995;
Agmon et al., 1996; Zhang et al., 1991). The depolariz-
ing inhibitory potentials seen in young animals are
probably due to the outward flow of Cl - through
GABA A or glycine receptor-coupled channels (Reich-
ling et al., 1994; Owens et al., 1996). Therefore, intra-
cellular chloride must be elevated in young neurons,
and it is important to understand how chloride is dis-
tributed across the membrane.
Intracellular chloride [Cl - ] i is regulated primarily by
two cation-chloride cotransporter family members: a
Na-K-2Cl cotransporter (NKCC1) leads to cytoplasmic
accumulation of chloride, and a K-Cl cotransporter
(KCC2) extrudes chloride (Payne et al., 2003). During
early development. [Cl - ] i is relatively high due to
NKCC1 activity (Clayton et al., 1998; Kanaka et al.,
2001). In LSO neurons, NKCC1 transports Cl - into the
cell, particularly in immature neurons, and this con-
tributes to the depolarizing IPSPs (Kakazu et al., 1999).
Similarly, Cl - is transported into Rohon-Beard cells
in the developing Xenopus spinal cord, leading to
GABA-evoked depolarizations (Rohrbough and
Spitzer, 1996).
As KCC2 expression increases, [Cl - ] i drops below the
electrochemical equilibrium (Lu et al., 1999; DeFazio et
al., 2000; Hübner et al., 2001). This event plays the great-
est role in the transition from inhibitory synapse-
evoked depolarizations to hyperpolarizations (Owens
et al., 1996; Ehrlich et al., 1999; Kakazu et al., 1999;
Rivera et al., 1999). The presynaptic terminal can influ-
ence chloride transporter expression or function. In
hippocampal cultures, GABA A receptor activation facili-
tates KCC2 expression and the appearance of GABA A -
mediated hyperpolarizations (Ganguly et al., 2001).
Neuron-specific KCC2 has a tyrosine phosphoryla-
tion consensus site (Payne, 1997), and its function may
be modulated during development. For example,
KCC2 is expressed at high levels in LSO neurons
during the time when they display depolarizing IPSPs
(Balakrishnan et al., 2003), suggesting that a post-
translational modification must be involved. It has
been found that cultured hippocampal neurons ini-
tially expressed an inactive KCC2 protein, which
becomes activated during maturation (Kelsch et al.,
2001). Activation of KCC2 in immature neurons can be
Up to this point, our discussion has focused on exci-
tatory synapses; these connections have provided the
great majority of information on synaptogenesis,
and most of that from the cholinergic NMJ. Initially,
it was thought that inhibitory synapses, those re-
leasing GABA or glycine, matured after excitatory
synapses. This is because IPSPs are often not observed
in neontal animals. For example, intracellular record-
ings from the kitten visual cortex demonstrate that
afferent-evoked IPSPs are absent from over half the
neurons during the first postnatal week, whereas all
neurons display IPSPs by adulthood (Komatsu and
Iwakiri, 1991). Similar observations have been made
on the developing rat neocortex (Luhman and Prince,
1991).
However, synaptic inhibition appears with a similar
time course as synaptic excitation in diverse areas such
as the spinal cord, cerebellar nuclei, olfactory bulb,
lateral superior olive, and somatosensory cortex
(Oppenheim and Reitzel, 1975; Sanes, 1993). Inhibitory
events are probably more difficult to detect in young
animals, both because they are concealed by excitatory
events (Agmon et al., 1996) and their equilibrium
potential is close to the resting membrane potential
(Zhang et al., 1991). Therefore, it is likely that
inhibitory synapses are present from the outset, but
their functional properties are immature.
IS INHIBITION REALLY INHIBITORY
DURING DEVELOPMENT?
In adult animals, inhibitory synaptic potentials are
generally hyperpolarizing. This is because the receptor
is coupled to a Cl - channel and the Cl - equilibrium
potential is more negative than the cells resting poten-
tial. However, inhibitory synaptic transmission usually
produces depolarizing potentials during the initial
phase of development (Obata et al., 1978; Bixby and
Spitzer, 1982; Mueller et al., 1983, 1984; Ben-Ari et al.,
1989). For example, during the first postnatal week, rat
hippocampal neurons display large spontaneous and
evoked depolarizations that are blocked by the GABA A
receptor antagonist, bicuculline (Figure 8.33A).
These depolarizing IPSPs are apparently large
enough to open voltage-gated calcium channels. In
dissociated cultures obtained from embryonic rat
hypothalamus, intracellular free calcium is decreased
by bicuculline during the first 10 days in vitro (Obri-
Search Pocayo ::




Custom Search