Activity-dependent regulation of axonal growth: Posttranscriptional control of the GAP-43 gene by the NMDA receptor in developing hippocampus

The intricate circuitry of the nervous system has been shown to be refined by activity-dependent processes often involving the glutamate N- methyl-D-aspartate (NMDA) receptor. NMDA receptor activity has been directly associated with axonal growth during development and in adult models of synaptic plasticity. The axonal growth-associated protein GAP-43 has been involved in the same processes as the NMDA receptor, but a direct link between the two has never been demonstrated in vivo. It is attractive to think that the NMDA receptor may regulate axonal growth through GAP-43. We tested this idea in outgrowing axons of hippocampal granule cells, the mossy fibers. Granule cells normally only express GAP-43 in an organized outside-in manner during a restricted period in postnatal development paralleling the pattern of axonal extension. Here, we show that during postnatal development in a transgenic mouse bearing a GAP-43 promoter/lacZ reporter construct, granule cells also display an outside-in pattern of promoter activation as indexed by transgene expression (PATE). In fact, PATE precedes axonal outgrowth with temporospatial fidelity. Since PATE deactivates on growth termination, the promoter may function as a switch for an intrinsic program of regulated axonal growth. The NMDA receptor antagonist MK-801 administered within a restricted time frame (4-8 days) results in a decrease in the extent and intensity of mossy fiber staining. While levels of GAP-43 mRNA are significantly reduced in granule cells, GAP-43 PATE is not. The level of GAP- 43 expression and axonal growth during development appears to be dually controlled by a transcriptional program that is activity-independent and by a posttranscriptional mechanism that is activity-dependent and NMDA mediated.