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FIGURE 8.33 The development of hyperpolarizing inhibition. GABAergic inhibition initially evokes
membrane depolization and calcium entry. A. Intracellular recording from a neonatal rat hippocampal neuron
shows that the GABA A receptor antagonist, bicuculline (BIC), blocks the spontaneous action potential and
causes the cell to hyperpolarize. B. Intracellular free calcium was monitored in hypothalamic cultures during
exposure either to glutamate receptor antagonists (AP5/CNQX) or to a GABA A receptor antagonist (BIC).
After 8 days in vitro (young neurons), only BIC produced a decrease in calcium. At 33 days in vitro (older
neurons), AP5/CNQX produced a decrease in calcium, and BIC increased calcium. C. Western blot shows
that KCC2 protein is developmentally upregulated in the telencephalon but not in the brainstem, where
expression is high from the outset (left). Immunohistochemical staining of rat LSO neurons (right) shows that
the KCC2 protein labeling is primarily intracellular at P0 (arrows), but the signal is at the plasma membrane
surrounding the somata and proximal dendrites at P21 (arrows). D. KCC2 was immunoprecipitated with a
KCC2 antiserum in cortex tissue from P3, P5, P9, and P30 mice. A Western analysis was performed on the
immunoprecipitate using either a KCC2 antibody (left) or a phosphotyrosine-antibody (right). (Adopted from
Ben-Ari et al., 1989; Obrietan and van den Pol, 1995; Balakrishnan et al., 2003; Stein et al., 2004)
induced by IGF-1 or a Src kinase, whereas membrane-
permeable protein tyrosine kinase inhibitors deacti-
vate KCC2. Therefore, endogenous protein tyrosine
kinases may mediate the developmental switch of
inhibitory responses by modifying KCC2. In fact, there
is an increase in both KCC2 protein expression and
tyrosine phosphorylation during normal development
of the mouse cortex (Stein et al., 2004). Finally, the
neurotrophin signaling system has been implicated in
regulating chloride transport. In transgenic embryonic
mice that overexpress BDNF under the control of the
nestin promoter, KCC2 expression increases dramati-
cally (Aguado et al., 2003). Interestingly, it appears that
BDNF may exert the opposite influence in older
animals (Rivera et al., 2002).
The generic cortical neuron with which we began
the chapter somehow manages to express just the right
complement of receptors and channels, and place them
at the correct part of the cell. As this chapter makes
clear, the differentiation of synapses and electrical
properties depends upon an ongoing discussion
between neuronal connections. Fortunately, we now
have a basic understanding of synapse formation,
including a few of these transynaptic signalling path-
ways. As extraordinary as these accomplishments are,
it is important to recognize that we have ignored most
of the modulatory afferents, many of the neurotrans-
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