Opposing roles for neurotrophin-3 in targeting and collateral formation ofdistinct sets of developing cortical neurons

Neurotrophin-3 and its receptor TrkC are expressed during the development o f the mammalian cerebral cortex. To examine whether neurotrophin-3 might pl ay a role in the elaboration of layer-specific cortical circuits, slices of layer 6 and layers 2/3 neurons were cultured in the presence of exogenousl y applied neurotrophin-3. Results indicate that neurotrophin-3 promotes axo nal branching of layer 6 axons, which target neurotrophin-3-expressing laye rs in vivo, and that it inhibits branching of layers 2/3 axons, which avoid neurotrophin-3-expressing layers. Such opposing effects of neurotrophin-3 on axonal branching were also observed with embryonic cortical neurons, ind icating that the response to neurotrophin-3 is specified at early developme ntal stages, prior to cell migration. In addition to its effects on fiber b ranching, axonal guidance assays also indicate that neurotrophin-3 is an at tractive signal for layer 6 axons and a repellent guidance cue for layers 2 /3 axons. Experiments with specific antibodies to neutralize neurotrophin-3 in cortical membranes revealed that endogenous levels of neurotrophin-3 ar e sufficient to regulate branching and targeting of cortical axons. These o pposing effects of neurotrophin-3 on specific populations of axons demonstr ate that it could serve as one of the signals for the elaboration of local cortical circuits.