Regulation of intrinsic regenerative properties and axonal plasticity in cerebellar Purkinje cells

Axon regeneration in the mammalian brain requires that injured neurons upregulate a specific set of growth-associated genes. To investigate the mechanisms that control the intrinsic growth properties of adult central neurons, we have examined the response to injury and regenerative potential of different cerebellar and precerebellar neuron populations. Axotomised neurons in the inferior olive, deep cerebellar nuclei and lateral reticular nucleus upregulate growth-associated molecules and regenerate their neurites into growth-permissive transplants. In contrast, Purkinje cells fail to respond to injury and show extremely poor regenerative capabilities. Targeted overexpression of GAP-43 promotes Purkinje axon plasticity, indicating that the weak regenerative potential of these neurons is mainly due to the inability to activate growth-associated genes. Application of neutralising antibodies against the myelin-associated protein Nogo-A induces cell body changes and axonal sprouting in intact Purkinje cells. In addition, immature injured Purkinje cells respond to axotomy and regenerate transected neurites, but they progressively lose this ability during postnatal development in parallel with myelin formation and the establishment of intracortical connections. These results indicate that the intrinsic growth potential of Purkinje cells is constitutively inhibited by environmental signals directed at stabilising the mature connectivity and preventing aberrant neuritic plasticity. Such a strict control eventually leads to restrict the regenerative capabilities of these neurons after injury.