Developmental Mechanisms That Generate Precise Patterns of Neuronal Connectivity

The functioning of the nervous system depends upon the underlying detailed and highly stereotyped patterns of neuronal connectivity. How these precise patterns of synaptic connections form during development is the subject of this review. The specificity of synaptic connections unfolds in three major steps: pathway selection, target selection, and address selection. First, the growing tips of neurons, the growth cones, traverse long distances to find their correct target region. En route, they are confronted by a series of choice points and yet correctly navigate these pathways in a remarkably unerring way. Once they reach the correct neighborhood, they contact and recognize their correct target, typically a regionally localized set of neurons. In this way, the overall scaffold of projections and synapses is initially established. But these initial patterns of connections are then refined, as axonal terminals retract and expand to select a specific subset of cells from. within the overall target. This remodeling, called address selection, relies on the context of and competition with surrounding inputs and is capable of transforming a coarse-grained and overlapping projection into a refined and highly tuned pattern of connections. Experiments over the last few decades have clarified the issue of how neural specificity is generated by suggesting that two broad mechanisms work in concert to orchestrate the formation of precise patterns of neural connections during development: those that require neuronal activity (activity dependent), and those that do not (activity independent). The initial steps of growth cone guidance typically occur before neurons become functionally active and rely on molecular mechanisms of pathway and target recognition that are largely activity independent. These mechanisms bring together multiple inputs with appropriate targets to form initial patterns of connections. From this point on, the patterns of neuronal activity within these emerging patterns of connections take over as the predominant mechanism that drives the refinement and remodeling of these initial projections into highly tuned and functioning circuits. This process of activity-dependent synaptic plasticity does not stop at birth but continues throughout the lifetime of the organism as the patterns of neural activity driven by input from the external world continue to modify the strength and structure of dendrites, axonal arbors, and synapses (e.g., Purves et al., 1986; Bailey and Chen, 1989). The growing evidence that adults and embryos may use common molecules and mechanisms to modify their synapses (Cline and ConstantinePaton, 1989; Mayford et al., 1992) has linked the once separate fields of developmental neurobiology and learning and memory. In this review, we consider the range of activityindependent and activity-dependent mechanisms that generate precision of neuronal connections. We then focus on two examples at opposite ends of the spectrum-the connections between motoneurons and muscles and between the retina and higher visual centers--to highlight the extent to which different parts of the nervous system use the same mechanisms but in different proportions to achieve the final specificity.