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 b efore encountering the inhibitor; priming cerebellar neurons with BDNF or G DNF, but not NGF, or priming DRG neurons with any of these neurotrophins bl ocks 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 e xposed to MAG/myelin and neurotrophins simultaneously, but with the G(i) pr otein inhibitor, inhibition is blocked. We suggest that priming neurons wit h particular neurotrophins elevates cAMP and activates PKA, which blocks su bsequent inhibition of regeneration and that priming is required because MA G/myelin activates a G(i) protein, which blocks increases in cAMP. This is important for encouraging axons to regrow in vivo.