Synaptic structure and development: The neuromuscular junction

Synaptic transmission--the process by which signals are transferred from a neuron to its target--is a fundamental function of neurons. Most neurobiologists look to the synapse to find the patterns of connectivity that account for neural specificity, the information processing that underlies behavior, and the plasticity responsible for learning. Accordingly, it is no surpris e that we are keenly interested in how synapses are formed. What is surprising is that virtually all of our current understanding of synaptogenesis derives from the study of just one synapse, the vertebrate skeletal neuromuscular junction. This synapse lies outside of the brain and does not even have a neuron as its postsynaptic element. It is the only synapse in vertebrates or invertebrates, however, whose structure and function are sufficiently well understood that the mechanisms regulating its development can be analyzed. The features of simplicity and accessibility that have enabled investigation of the mature synapse facilitate this analysis. In addition, unlike central neurons, muscles are readily reinnervated following nerve damage, allowing synaptogenesis to be studied in the adult, uncomplicated by processes such as neurogenesis that occur only in the embryo. Finally, although interneuronal synapses differ from neuromuscular junctions in important ways, our fragmentary knowledge to date encourages the belief that similar principles govern the development of both. For all of these reasons, this review is devoted to the neuromuscular junction. We begin by describing the cytological and molecular architecture of this synapse, making three main points: that chemical synapses are designed for rapid, focal transmission of information; that this task is performed by highly specialized preand postsynaptic domains that lie in precise juxtaposition across the synaptic cleft; and that many of the components forming these domains have now been isolated and characterized. We then examine the complex series of inductive interactions between nerve and muscle that regulate synaptic development. These interactions are mediated by membrane, extracellular matrix, and soluble molecules that are only now being identified. A major point is that nerve and muscle can each synthesize and assemble synaptic components on its own. In vivo, however, they do so in coordination and only at points of juxtaposition. Thus, intercellular interactions during synaptogenesis localize and refine the synaptic functions of each cell. The result is a process of synaptic maturation that proceeds to completion in a series of overlapping steps over a prolonged interval. As the signaling molecules are identified and the regulatory circuits that define these steps are unraveled, the classic histological and physiological descriptions of synaptogenesis are being reformulated in molecular and mechanistic terms.