Apoptosis or neural pruning: Distinct mechanisms for cell and axon-specific degeneration.

Researchers at the University of North Carolina have obtained evidence suggesting distinct neuronal pathways lead to either whole cell death via apoptosis or selective axon degeneration (pruning). This finding could lead to treatments for neurodevelopmental diseases with aberrant axon pruning, such as autism and schizophrenia.

 
Neuronal apoptosis and axon pruning are part of normal development. It is believed that their main purpose is to create specific and mature neuronal circuitry by removing unnecessary structures, and so aid learning and memory. Apoptotic pathways are restricted after development to allow neurones to survive for as long as the organism lives. However, pruning is important both during development and in later life; it not only acts to establish specific neuronal connections, but also changes this circuitry as learning occurs – a phenomenon known as plasticity.
 

Both pathways rely on molecules called caspases to induce degeneration. The research team, led by Mohanish Deshmuck, placed mouse neurones in microfluidic chambers to manipulate neuronal environment. They discovered that caspase-6 activation led to apoptosis or pruning depending on nerve growth factor (NGF) levels: If NGF was withdrawn from around the axon, pruning occurred. However, the neurone underwent apoptosis if NGF was also withdrawn from around the cell body. Furthermore, it was seen that the activator Apaf-1 is not required in pruning as it is in apoptosis, indicating that there is another unknown mechanism by which caspases are activated.
 

Pathological axon pruning is thought to underlie some neurological disorders. With autism, it is thought that there is a failure in pruning during brain development, whilst excessive pruning is seen in those with schizophrenia. These diseases currently have no cure, but modulation of caspase activity has been suggested as a potential therapeutic strategy to be explored in future research.