BDNF modulates, but does not mediate, activity-dependent branching and remodeling of optic axon arbors in vivo

The proper development of axon terminal arbors and their recognition of tar get neurons depend, in part, on neuronal activity. Neurotrophins are attrac tive candidate signals to participate in activity-dependent development and refinement of neuronal connectivity. In the visual system, brain-derived n eurotrophic factor (BDNF) has been shown to modulate the elaboration and re finement of axonal arbors and to participate in the establishment of topogr aphically ordered visual maps. By examining in vivo with time-lapse microsc opy the effects of activity blockade and BDNF on optic axon arborization, I show that the dynamic mechanisms by which neurotrophins and neuronal activ ity regulate axon arborization differ. Acute retinal activity blockade by i ntraocular injection of tetrodotoxin (TTX) rapidly and significantly increa sed branch addition and elimination, thus interfering with axon branch stab ilization. The effects of activity blockade on branch dynamics resulted in increased arbor complexity in the long term and were prevented by altering endogenous BDNF levels at the target. BDNF promoted axon arborization by in creasing branch addition and lengthening, without affecting branch eliminat ion. Activity blockade, however, did not prevent the growth-promoting effec ts of BDNF, indicating that BDNF can affect axon arborization even in the a bsence of activity. Together this evidence indicates that BDNF acts as a mo dulator, but not as a direct mediator, of activity during the morphological development of neurons. Consequently, neuronal activity and BDNF use disti nct but interactive mechanisms to control the development of neuronal conne ctivity; BDNF modulates axon arborization by promoting growth, neuronal act ivity participates in axon branch stabilization, and together these two sig nals converge to shape axon form.