Clearly, the presynaptic terminals are carrying on a rather hostile conversation through the postsynaptic cell, and there must be some molecular pathway that conveys the signal from one contact to another through the cytoplasm. One hypothesis is that depolarizing synaptic potentials open voltage-gated Ca2+ channels, and Ca2+-dependent proteolytic enzymes are recruited to demolish the nonactive terminals, ultimately leading to their withdrawal. A variety of proteolytic enzymes have been discovered in the nerve terminals and somata of developing neurons. This hypothesis was tested at the mammalian NMJ by decreasing extracellular Ca2+ or blocking specific Ca2+-activated proteases, and both manipulations were able to slow down the process of synapse elimination (Connold et al., 1986).
Once again, there are important similarities between synapse elimination and heterosynaptic depression (above). First, it is possible to prevent heterosynaptic depression by injecting the muscle cell with a Ca2+ chelator that sops up free Ca2+, suggesting that a rise in postsynaptic calcium is necessary for depression to occur. Second, it is possible to cause synaptic depression by momentarily raising postsy-naptic calcium. This was accomplished by loading muscle cells with molecules of "caged" calcium, which can release the calcium into the cytoplasm when it is exposed to ultraviolet light (Figure 9.26A). Therefore, the synaptic responses at one muscle cell are recorded while a second neighboring muscle cell is exposed to a brief pulse of UV light, and synaptic transmission is depressed by 50% within seconds (Figure 9.26B) (Lo and Poo, 1994; Cash et al., 1996). Interestingly, this rise in postsynaptic calcium is only effective within 50 mm of the synapse, and stimulation of the synapse protects it from depression (Figure 9.26C).
Since synaptic activity leads to the depression and withdrawal of neighboring synapses, it follows that the active synapse must somehow be protected. Although the signaling pathways that lead to AChR loss and het-erosynaptic depression are not fully understood, there is evidence that two kinases, PKA and PKC, are involved (Figure 9.25C). For example, PKC activators can produce synaptic depression in the absence of stimulation. In contrast, the PKC activator has no effect when the neuron is stimulated (Li et al., 2001). There are probably several molecular changes that attend synapse elimination at the nerve-muscle junction. The removal of AChRs, a decrease in ACh release, and loss of adhesion between pre- and postsynaptic cells (see below), all conspire to weaken the connection.
FIGURE 9.26 Synapse depression depends on postsynaptic calcium. A. A whole-cell recording is made from an innervated myocyte (Muscle 1), while the intracellular calcium was elevated in a second nearby myocyte (Muscle 2). Calcium was elevated by first filling Muscle 2 with caged calcium and then using UV light to release the calcium from its "cage". B. Baseline nerve-evoked synaptic currents (downward deflections beneath each dot which represent the stimuli) are first recorded from Muscle 1 (black). When intracellular calcium is elevated in Muscle 2 by exposure to UV light, the nerve-evoked synaptic currents (red) become depressed within seconds. Depression is greatest when the muscles are within 50 mm of one another. C. A summary of three conditions shows that synaptic currents decline by 50% when calcium is elevated (red bar), but the effect can be abolished by stimulating the nerve during UV-evoked uncaging (blue). (Adapted from Cash et al., 1996)
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