Abstract

Dysregulation of synaptic structure and function forms the basis for many neurological disorders creating an urgent need to determine the mechanisms underlying functional reorganisation of the CNS . Coupled with synaptic decline, degeneration of the axonal compartment, as opposed to cell death, often precedes or is associated with the appearance of symptoms of disease. Understanding the mechanisms of axonal response to injury therefore becomes imperative in detecting and understanding the early stages of disease. Major efforts in this field have so far concentrated on spinal cord injury models. To gain a comprehensive view of axonal responses to injury in the adult CNS , we induced discrete axonal lesions in the intact brain. By combining neuron-specific green fluorescent protein transgenic mice and in vivo 2-Photon microscopy through a cranial window we monitored the temporal dynamics of reorganisation of the surviving neuron and the degeneration of the disconnected axon. We find that lesions can be targeted to identified axons. Most disconnected axons (75%) degenerate rapidly within 24h, with the remaining 25% degenerating within 48h. Degeneration of the proximal part is local, comprising 30-400 microns from the lesion site. There is no attempt of growth from the proximal end up to three weeks post-lesion. We are in the process of quantifying 1) synaptic remodelling in the proximal side and 2) the induced damage in terms of cell death, sub-cellular damage, glia responses.