Electrical activity, growth cone motility and the cytoskeleton.

Abstract

The development of the nervous system takes place in two main steps: first an extensive preliminary network is formed and then it is pruned and trimmed to establish the final form. This refinement is achieved by mechanisms that include cell death, selective growth and loss of neurites and the stabilization and elimination of synapses. The focus of this review is on selective neurite retraction during development, with particular emphasis on the role of electrical activity. In many developing vertebrate and invertebrate neurones, the frequency and duration of ongoing impulse activity determine the final arborizations and the pattern of connections. When impulse traffic is silenced, axons fail to retract branches that had grown to inappropriate destinations in the mammalian visual system, cerebellum and neuromuscular junctions. Similarly, in crustaceans, Drosophila melanogaster and leeches, refinements in axonal morphology during development are influenced by impulse activity. From experiments made in culture, it has been possible to mimic these events and to show a clear link between the density of voltage-activated calcium channels in a neurite and its retraction following stimulation. The distribution of these calcium channels in turn is determined by the substratum with which the neurites are in contact or by the formation of synapses. Several lines of evidence suggest that calcium entry into the growth cone leads to collapse by disruption of actin filaments. One candidate for coupling membrane events to neurite retraction is the microfilament-associated protein gelsolin which, in its calcium-activated state, severs actin filaments. Open questions that remain concern the differential effects of activity on dendrites and axons as well as the mechanisms by which the growth cone integrates information derived from stimuli in the cell and in the extracellular environment.