Neuronal Cyclic AMP Controls the Developmental Loss in Ability of Axons to Regenerate

Abstract

Unlike neonatal axons, mammalian adult axons do not regenerate after injury. Likewise, myelin, a major factor in preventing regeneration in the adult, inhibits regeneration from older but not younger neurons. Identification of the molecular events responsible for this developmental loss of regenerative capacity is believed key to devising strategies to encourage regeneration in adults after injury. Here, we report that the endogenous levels of the cyclic nucleotide, cAMP, are dramatically higher in young neurons in which axonal growth is promoted both by myelin in general and by a specific myelin component, myelin-associated glycoprotein (MAG), than in the same types of neurons that, when older, are inhibited by myelin-MAG. Inhibiting a downstream effector of cAMP [protein kinase A (PKA)] prevents myelin-MAG promotion from young neurons, and elevating cAMP blocks myelin-MAG inhibition of neurite outgrowth in older neurons. Importantly, developmental plasticity of spinal tract axons in neonatal rat pups in vivo is dramatically reduced by inhibition of PKA. Thus, the switch from promotion to inhibition by myelin-MAG, which marks the developmental loss of regenerative capacity, is mediated by a developmentally regulated decrease in endogenous neuronal cAMP levels.

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

“…In 1994, a well-known myelin protein, myelin-associated glycoprotein (Mag), was shown to be a potent inhibitor of neurite outgrowth in culture 16,17 . Interestingly, young neurons are not inhibited by Mag; in fact, their growth is promoted in most cases [17][18][19][20][21] . Therefore, Mag seems to be bifunctional, and all neurons that have been studied to date switch their response to Mag from promotion to inhibition with development.…”

“…Therefore, Mag seems to be bifunctional, and all neurons that have been studied to date switch their response to Mag from promotion to inhibition with development. The age at which the switch occurs is specific to the particular neuron type, and the ability of young neurons to grow on Mag (and on myelin in general) correlates with their ability to regenerate spontaneously in vivo 18 (see later in text).…”

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…140 Both Arginase 1 and cAMP levels are high in young (neonatal) DRG neurons, correlating well with their ability to elongate in the presence of MAG. 146,147 Rolipram, a compound previously tested in clinical trials for treatment of depression, 148 is a phosphodiesterase inhibitor, and thus causes cAMP to accumulate by preventing its enzymatic degradation. Rolipram has recently been administered systemically after SCI in rats, with encouraging results; 149,150 the central role of Rolipram in recent reports of combination approaches stimulating regeneration and functional recovery are discussed below (see 'Casting the combination').…”

Repair of spinal cord injuries: where are we, where are we going?

“…11 The reasons for the poor regenerative response of CNS axons is not known. To some extent the di erence between the regenerative response in the CNS and PNS can be ascribed to factors released by damaged peripheral nerves that stimulate regeneration, and the ability of the axon to overcome inhibitory environments depends on levels of cAMP and other signalling molecules, 12 but fundamental issues remain unsolved.…”

“…Blocking Rho has been successful at promoting regeneration in the spinal cord and optic nerve, 31,32 and increasing levels of cAMP also promotes axon regeneration. 12 One of the issues a ecting the regenerative response of axons that is not yet understood is the di erence in response when axons are cut close to the cell body or further away. In general, CNS axons regenerate more successfully if they are cut close to their cell body.…”