and made whole-cell voltage clamp recordings in vitro to monitor the efficacy of synaptic transmission (56). Ganglion cell axons were stimulated by inserting electrodes into the optic tract, just adjacent to the LGN in the slice. Three to six bursts of high frequency stimulation of the optic tract caused a significant enhancement of retinogeniculate synaptic transmission that lasted for several tens of minutes to an hour in about 40% of all the cells recorded. Examples of such enhancement of transmission, recorded from ferret LGN slices, are shown in Fig. 6. In some instances, we could also prevent this increase by using 2-amino-5-phosphonovaleric acid to block N-methylD-aspartate (NMDA) receptors, known to be present in LGN neurons at this age (56–58). Blockade of NMDA receptors in vivo between P14 and P21 is also known to prevent the final refinement of retinal ganglion cell axons into sublayers receiving input from on-center or off-center ganglion cells (38). Thus, these observations suggest that the activity-dependent synaptic enhancement observed in vitro could indeed represent a cellular mechanism underlying the process of segregation of ganglion cell axons within the LGN.
In some ways these experiments have raised more questions than they have answered. Is the stereotyped bursting pattern of firing of retinal ganglion cells the most effective pattern for evoking synaptic enhancement? What are the long-term consequences of enhancement of synaptic transmission —e.g., does it result in morphological change? To what extent is the cellular mechanism underlying synaptic strengthening during development similar to that known to occur in the hippocampus during long-term potentiation (59)? And finally, is there a process of activity-dependent weakening of synaptic transmission since, as discussed above, some of the synaptic contacts between retinal ganglion cells and LGN neurons that are present early on are ultimately eliminated.
The development of retinogeniculate connections in mammals is one of many examples in which the adult pattern of connections is not established initially but rather is sculpted from an immature pattern. Here, I have put forward the argument that the formation of the adult pattern of the eye-specific layers in the mammalian LGN requires activitydriven competitive interactions between ganglion cell axons from the two eyes for common postsynaptic neurons. Of course, this cannot be the whole story since the layers always form in the same pattern and since there is also a segregation of subtypes of functionally distinct retinal ganglion cell axons within different layers and from each other even within the same layer. Just how many of these other important details of LGN organization may be accounted for by timing differences in the generation of different classes of retinal ganglion cells (60), by competitive interactions between ganglion cells within the same eye (61), or by specific molecular differences between cells remain to be determined. Nevertheless, the implication that activity-driven competition plays an essential role in wiring of the visual system even before vision raises the possibility that spontaneous neural activity may shape connections elsewhere in the nervous system during fetal development.
The requirement for neuronal activity in producing the adult precision of connections is a genetically conservative means of achieving a high degree of precision in wiring. To specify precisely each neural connection between retina and LGN by using specific molecular markers would require an extraordinary number of genes, given the thousands of connections that are formed. The alternative, to specify precise pathways and targets with molecular cues and then using the rules of activity-dependent sorting to achieve ultimate precision in connectivity, is far more economical. Indeed, once axons recognize and grow into their appropriate targets, the same general rules of activity-dependent competition can apply throughout the nervous system. A major challenge for the future will be to elucidate the cellular and molecular bases for these rules.
I wish to thank the many colleagues and collaborators whose essential contributions made this review article possible, including D. Baylor, G. Campbell, M. Feller, R. Gallego, P. A. Kirkwood, D. V. Madison, M. Meister, R. Mooney, A. Penn, M. Siegel, D. W. Sretavan, M. P. Stryker, R. O. L. Wong, and R. M. Yamawaki. The original research work presented in this article was supported in part by grants from the National Institutes of Health (EY02858 and MH48108), the National Science Foundation (IBN92-12640), and the March of Dimes. C.J.S. is an investigator of the Howard Hughes Medical Institute.
1. Goodman, C. S. & Shatz, C. J. ( 1993) Cell 72/ Neuron 10, 1–20.
2. Rodieck, R. W. ( 1979) Annu. Rev. Neurosci. 2, 193–255.
3. Sherman, S. M. ( 1985) Prog. Psychobiol. Physiol. Psychol. 11, 233–313.
4. Rakic, P. ( 1977) Philos. Trans. R. Soc. London B 278, 245–260.
5. Linden, D. C., Guillery, R. W. & Cucchiaro, J. ( 1981) J. Comp. Neurol. 203, 189–211.
6. Shatz, C. J. ( 1983) J. Neurosci. 3, 482–499.
7. Sretavan, D. W. & Shatz, C. J. ( 1986) J. Neurosci. 6, 234–251.
8. Rakic, P. ( 1981) Science 214, 928.