Activity-driven sharpening of the retinotectal projection: the search for retrograde synaptic signaling pathways

Patterned visual activity, acting via NMDA receptors, refines developing retinotectal maps by shaping individual retinal arbors. Because NMDA receptors are postsynaptic but the retinal arbors are presynaptic, there must be retrograde signals generated downstream of Ca(++) entry through NMDA receptors that direct the presynaptic retinal terminals to stabilize and grow or to withdraw. This review defines criteria for retrograde synaptic messengers, and then applies them to the leading candidates: nitric oxide (NO), brain-derived neurotrophic factor (BDNF), and arachidonic acid (AA). NO is not likely to be a general mechanism, as it operates only in selected projections of warm blooded vertebrates to speed up synaptic refinement, but is not essential. BDNF is a neurotrophin with strong growth promoting properties and complex interactions with activity both in its release and receptor signaling, but may modulate rather than mediate the retrograde signaling. AA promotes growth and stabilization of synaptic terminals by tapping into a pre-existing axonal growth-promoting pathway that is utilized by L1, NCAM, N-cadherin, and FGF and acts via PKC, GAP43, and F-actin stabilization, and it shares some overlap with BDNF pathways. The actions of both are consistent with recent demonstrations that activity-driven stabilization includes directed growth of new synaptic contacts. Certain nondiffusible factors (synapse-specific CAMs, ephrins, neurexin/neuroligin, and matrix molecules) may also play a role in activity-driven synapse stabilization. Interactions between these pathways are discussed.