Neurotrophins enhance electric field-directed growth cone guidance and directed nerve branching

Neurotrophins play major roles in the developing nervous system in controlling neuronal differentiation, neurite outgrowth, guidance and branching, synapse formation and maturation, and neuronal survival or death. There is increasing evidence that nervous system construction takes place in the presence of dc electric fields, which fluctuate dynamically in space and time during embryonic development. These have their origins in the neural tube itself, as well as in surrounding skin and gut. Early disruption of these endogenous electric fields causes failure of the nervous system to form, or else it forms aberrantly. Nerve growth, guidance, and branching are controlled tightly during pathway construction and in vitro dc electric fields have profound effects on each of these behaviours. We have used cultured neurones to ask whether neurotrophins and dc electric fields might interact in shaping neuronal growth, given their coexistence in vivo. Electric field-directed nerve growth generally was enhanced by the simultaneous presentation of several neurotrophins to the growth cone. Under certain circumstances, more nerves turned cathodally, they turned faster, further, and in lower field strengths. Intriguingly, other combinations of dc electric field and neurotrophins (low field strength and neurotrophin 3 (NT-3) switched the direction of growth cone turning. Additionally, cathodally directed nerve growth was faster and directed branching was much more common when electric fields and neurotrophins interacted with neuronal growth cones. Given such profound changes in growth cone behaviour in vitro, neurotrophins and endogenous electric fields are likely to interact in vivo.