Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism

MAG is a potent inhibitor of axonal regeneration. Here, inhibition by MAG, and myelin in general, is blocked if neurons are exposed to neurotrophins before encountering the inhibitor; priming cerebellar neurons with BDNF or GDNF, but not NGF, or priming DRG neurons with any of these neurotrophins blocks inhibition by MAG/myelin. Dibutyryl cAMP also overcomes inhibition by MAG/myelin, and cAMP is elevated by neurotrophins. A PKA inhibitor present during priming abrogates the block of inhibition. Finally, if neurons are exposed to MAG/myelin and neurotrophins simultaneously, but with the G(i) protein inhibitor, inhibition is blocked. We suggest that priming neurons with particular neurotrophins elevates cAMP and activates PKA, which blocks subsequent inhibition of regeneration and that priming is required because MAG/myelin activates a G(i) protein, which blocks increases in cAMP. This is important for encouraging axons to regrow in vivo.