Experiments performed on simple invertebrate circuits 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 excitatory synaptic activity is increased by growing the cultures 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 equilibrium 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 of ligand- and voltage-gated channels, as well as transmitter 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 surgically 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 potential 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), suggesting 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 excitability 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 developmental manipulation. For example, one can selectively decrease inhibition to an auditory brainstem nucleus called the LSO (circuit shown in Figure 8.28) by ablating 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,
FIGURE 9.30 Elimination of inhibitory synapses during development. A. The schematic shows a nucleus in the ventral auditory brain stem (MSO) that receives inhibitory synapses from two nearby nuclei (LNTB and MNTB). B. At birth, inhibitory terminals are located on the soma and dendrites of MSO neurons. However, most of the dendritic synapses are eliminated during postnatal development (top left). The micrograph (top right) shows stained MSO neurons and glycine receptors from an adult animal. The glycine receptors (yellow) are largely restricted to the soma, and very few remain on the dendrites (blue). When animals are deafened unilaterally during development, the elimination of inhibitory synapses fails to occur (bottom left). The micrograph shows that significant glycine receptor staining (yellow) is now found on the dendrites (bottom right). Scale bars are 20 mm. (From Kapfer et al., 2002)
and it is possible that such a manipulation produces a different sort of neuronal response. Alternatively, the homeostatic response may depend on the state of maturation (Burrone et al., 2002).
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