Synaptic Transmission At The Target

Some of the earliest experimental manipulations of target size suggested that functional synaptic contacts were correlated with survival. Removal of the nasal placodes in salamander embryos did not, at first, decrease the size of the innervating forebrain region. However, after the system became functional, loss of the target did produce a hypoplasia (Burr, 1916). Observations from the NMJ also suggest that functional synapses are involved in motor neuron survival. There is a very tight correlation between the onset of neuromuscular activity in chicks and the onset of normal motor neuron cell death.

If synapse activity at the target is necessary for survival, then one would predict that more neurons would die in its absence. To test this hypothesis, chick embryos were treated with an acetylcholine receptor (AChR) antagonist (curare or bungarotoxin) during a four- day period that overlapped the normal period of motor neuron death. Curare was quite effective at blocking neuromuscular transmission, as spontaneous movements were virtually eliminated for much of the treatment period. Rather than increasing cell death, the surprising result was that synapse blockade saved motor neurons (Figure 7.29). Over 90% of the motor neurons that would have died were still alive after the period of normal cell death ended and the curare had been removed. This effect is due to the interaction at the neuromuscular junction because agents that block AChRs in the CNS do not prevent cell death (Pittman and Oppenheim, 1979; Oppenheim et al., 2000). Furthermore, curare produced a threefold increase in the number of motor axon branches and synapses during the period when normal cell death occurs (Dahm and Landmesser, 1991). A similar decrease in normal cell death is found in the isthmo-optic nucleus when activity is blocked in its target, the eye, by injecting TTX during development (Pequignot and Clarke, 1992).

FIGURE 7.30 Electrical activity enhances the survival of embryonic cortex neurons by way of a neurotrophic signal. When the cultures are depolarized by adding KCl to the culture media, calcium enters the neurons, and the level of BDNF expression increases, leading to greater neuron survival compared to control media. The trophic influence of depolarization is eliminated by adding a function-blocking anti-BDNF antibody to the growth medium. (Adopted from Ghosh et al., 1994)

FIGURE 7.29 Blocking synaptic transmission prevents normal motor neuron cell death. A. Neuromuscular transmission can be blocked by applying curare onto the chorioallantoic membrane of chick embryos. B. In control animals, over 30% of motor neurons die after embryonic day 5. When animals are treated with curare from E6-9, the magnitude of normal cell death is greatly diminished. (Panel B adopted from Pittman and Oppenheim, 1979)

FIGURE 7.30 Electrical activity enhances the survival of embryonic cortex neurons by way of a neurotrophic signal. When the cultures are depolarized by adding KCl to the culture media, calcium enters the neurons, and the level of BDNF expression increases, leading to greater neuron survival compared to control media. The trophic influence of depolarization is eliminated by adding a function-blocking anti-BDNF antibody to the growth medium. (Adopted from Ghosh et al., 1994)

Thus, neuron survival may depend on proper access to the target-derived survival factor rather than on the total amount of factor produced by the target (Oppenheim, 1989). Access could result from a greater number of synapses. In fact, several observations suggest that synapse activity and survival factor expression are entwined with one another. Embryonic hippocampal neurons grown in dissociated culture for seven days make numerous synaptic contacts with each other, and the expression of NGF and BDNF mRNA gradually increases over this period. This neurotrophin expression is influenced by synaptic activity: NMDA receptor blockade decreases neurotrophin expression, whereas GABAa receptor blockade increases it (Zafra et al., 1991). Muscle cell expression of the neurotrophin, NT-4, is also regulated by synaptic activity, and the morphology and function of neuromuscular synapses depends on this signal (Funakoshi et al., 1995; Bellu-ardo et al., 2001; Gonzalez et al., 1999). It is possible that activity-dependent regulation of this neurotrophin permits motor neuron synapses to obtain access to a second factor that mediates survival.

The activity-dependent expression of BDNF has been shown to support embryonic cortex neuron survival in a culture dish (Figure 7.30). BDNF expression and survival depend on the entry of calcium into the neurons when they are depolarized in a medium containing a high potassium ion concentration. When function-blocking antibodies directed against BDNF are added to these cultures, the trophic effect of depolarization is eliminated (Ghosh et al., 1994). Therefore, neurons may have some influence over the survival factors that they seek from a target: increased branching may provide better access, and synaptic transmission can regulate the amount of factor produced.

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