Anterograde transport of neurotrophin proteins in the CNS--a reassessment of the neurotrophic hypothesis.

The basic tenets of the neurotrophic hypothesis are that i) limiting quantities of a given factor are produced in specific target tissues; ii) responsive neurons projecting to these targets compete for the limiting amounts of the factor; iii) the factor is bound within the target by selective receptors on afferent terminals, internalized, and retrogradely transported to the neuronal cell body where it provides signals affecting neuronal survival and differentiation. Although originally formulated on the basis of evidence for NGF's actions on peripheral sensory and sympathetic neurons, the neurotrophic hypothesis appeared to be upheld for CNS neuronal systems as well, where NGF was found to function primarily as a target-derived trophic factor for basal forebrain cholinergic neurons. With the discovery of additional neurotrophins sharing considerable structural homology with NGF, the question arose of whether the neurotrophic hypothesis held true for all members of this protein family. Recent investigations into the localization and function of neurotrophins other than NGF, particularly BDNF and NT-3, have provided evidence indicating that these molecules may not act in a manner consistent with the neurotrophic hypothesis, as originally postulated. Numerous studies in the peripheral and central nervous systems have now demonstrated that BDNF (and NT-3) may be preferentially trafficked anterogradely along axonal processes and stored within pre-synaptic terminals. Other studies have suggested that these factors may be released in an activity-dependent, rather than constitutive, manner and can act in autocrine or paracrine fashions to subserve an assortment of biological functions including anterograde effects on cell survival and differentiation, as well as more novel roles in synaptic transmission. These recent findings strongly suggest that, while the various neurotrophin proteins may be grouped into a single family based upon their structural homology, they should be considered as a heterogeneous group of trophic factors based upon function and mode of action.