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nation may involve an intermediate state, one in which
the synapse is anatomically present but cannot be
detected with functional criteria.
of ligand- and voltage-gated channels, as well as trans-
mitter release, all depend on postsynaptic activity levels.
What is the evidence that synaptic strength is
adjusted by a similar homeostatic mechanism in vivo?
To answer this question, direct measures of EPSP and
IPSP amplitudes have been made in a brain slice
preparation following a period of sensory deprivation
(e.g., blindness or deafness). When gerbils are surgi-
cally deafened before they would first experience
sound, compensatory responses are observed for both
excitatory and inhibitory synapses within the inferior
colliculus. Inhibitory synaptic conductance declines,
and the inhibitory reversal potential depolarizes. In
contrast, afferent-evoked excitatory synaptic responses
become larger and longer in duration (Vale and Sanes,
2000, 2002). Interestingly, the inhibitory reversal poten-
tial appears to become depolarized because chloride
transport is downregulated (Vale et al., 2003). Similar
observations have been made in the cortex. During
normal development of the rat visual cortex, the
amplitude of miniature EPSCs declines during the first
three postnatal weeks. However, when rat pups are
reared in complete darkness, this reduction in mEPSC
amplitude is largely prevented (Desai et al., 2002), sug-
gesting a compensatory response to the lost visual
drive. Dark rearing also prevents the normal increase
of inhibitory synaptic currents in Layer 2/3 cells
(Morales et al., 2002). In the auditory cortex of deaf
gerbils, there are three major compensatory responses
that may sustain an operative level of cortical excitabil-
ity in Layer 2/3 pyramidal neurons: the excitatory
synaptic response becomes longer in duration, the
inhibitory synaptic response becomes smaller in
amplitude, and there is a modest depolarization of the
resting membrane potential and increase in membrane
resistance (Kotak et al., 2005).
The homeostatic mechanism does not explain some
alterations in synaptic strength following a develop-
mental manipulation. For example, one can selectively
decrease inhibition to an auditory brainstem nucleus
called the LSO (circuit shown in Figure 8.28) by ablat-
ing the contralateral ear. The strength of synaptic
transmission was then measured with whole-cell
recordings using an acute brain slice preparation. In
normal animals, electrical stimulation of the inhibitory
pathway produced large IPSPs, but following a short
period of disuse the IPSPs were small or absent.
Interestingly, the unmanipulated excitatory pathway
became much stronger, displaying large NMDAR-
dependent EPSPs (Kotak and Sanes, 1996). A home-
ostasis mechanism should have upregulated the
inhibition and downregulated the excitation. The
selective deprivation of an inhibitory pathway is not
easily accomplished elsewhere in the nervous system,
Experiments performed on simple invertebrate cir-
cuits and dissociated cortical neurons show that
synapses and ion channels can each be regulated by the
average level of postsynaptic activity (Marder and
Prinz, 2002; Burrone and Murthy, 2003). This form of
plasticity is homeostatic; its purpose is to keep the
average postsynaptic discharge rate at about the same
level, and it continues to operate in the adult nervous
system (Royer and Pare, 2002). When postsynaptic
activity is increased or decreased, voltage- and ligand-
gated channels are adjusted to resist the manipulation.
For example, cortical neurons that are cultured with the
sodium channel blocker, TTX, increase their sodium
channels and decrease their potassium channels.
Similarly, excitatory synaptic currents increase and
inhibitory currents decrease when cultures are grown
in an assortment of activity blockers (Rao and Craig,
1997; Desai et al., 1999; Murthy et al., 2001; Kilman et
al., 2002; Burrone et al., 2002). Conversely, when exci-
tatory synaptic activity is increased by growing the cul-
tures in GABA and glycine receptor antagonists, the
amount of synaptic AMPA receptors declines and
spontaneous EPSCs are smaller (O'Brien et al., 1998).
A change in postsynaptic activity can also affect
the presynaptic terminal. In cultured hippocampal
neurons, activity blockade leads to an increase in the
size of the presynaptic terminal and docked vesicles as
measured with electron microscopy. In one study, these
changes were accompanied by an increase in presynap-
tic efficacy (Murthy et al., 2001). Homeostatic changes
in presynaptic release have also been demonstrated
in vivo. In congenitally deaf mice, there is an increase in
release probability at the very first central synapse in
the cochlear nucleus (Oleskevich and Walmsley, 2002).
In an imaginative genetic manipulation, fruit fly muscle
fibers were silenced by causing them to overexpress an
inwardly rectifying potassium channel; this drives the
resting membrane potential to the potassium equilib-
rium potential. The hyperpolarized muscle is no longer
able to reach action potential threshold, yet motor neuron-
evoked synaptic potentials are just as large as those
recorded in wild-type flies. In this case, there is an
increase in presynaptic release, with no change in
quantal size (Paradis et al., 2001). Therefore, the balance
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