Adjusting Glial Cell Behavior to Promote Axon Regrowth

One of the reasons why injuries to the nervous system are poorly regenerated at best is that the regrowth of axons, long connections between neurons, is hindered by scarring. The formation of neural tissue scarring is mediated by glial cells such as astrocytes. Researchers here demonstrate that it is in principle possible to adjust the behavior of these cells in order to reduce scar formation and promote successful axon regrowth following injury.

Glial cells carry out a variety of support and maintenance functions, and one type in particular - the astrocytic glial cell - has the unique ability to form scar tissue around damaged neurons. The presence of scar tissue is associated with inhibitory effects on the regrowth of mature neurons that are damaged by spinal cord injury. Recent evidence suggests, however, that these inhibitory effects are reversible, and in new work, scientists show that astrocytic glial cells can in fact play a major role in facilitating neuron repair.

The research is the first to establish a link between glucose metabolism in glial cells and functional regeneration of damaged neurons in the central nervous system. Scientists set out to investigate how scar tissue formation induced by glial cells impacts axon regeneration, using both fly and mouse models of axon injury. In initial experiments, they confirmed that the negative effects of glial cell activity on axon regeneration are indeed reversible. But the researchers also found that the switch between positive and negative effects on axon regrowth is directly related to the glial cells' metabolic status.

In follow-up experiments in flies, the researchers focused specifically on glycolysis - the metabolic pathway responsible for the breakdown of glucose - and discovered that upregulating this pathway alone in glial cells was sufficient to promote axon regeneration. This same result was observed in mice. Further investigation in fly and mouse models led to the identification of two glucose metabolites, lactate and hydroxyglutarate, that act as key mediators of the glial switch from an inhibitory reaction to a stimulatory response. "In the fly model, we observed axon regeneration and dramatic improvements in functional recovery when we applied lactate to damaged neuronal tissue. We also found that in injured mice, treatment with lactate significantly improved locomotor ability, restoring some walking capability, relative to untreated animals."

Experiments revealed that when glial cells are activated, they release glucose metabolites, which subsequently attach to molecules known as GABAB receptors on the neuron surface and thereby activate pathways in neurons that stimulate axon growth. "Our findings indicate that GABAB receptor activation induced by lactate can have a critical role in neuronal recovery after spinal cord injury. Moreover, this process is driven by a metabolic switch to aerobic glycolysis, which leads specifically to the production of lactate and other glucose metabolites."

Link: https://medicine.temple.edu/news/temple-researchers-discover-new-path-neuron-regeneration-after-spinal-cord-injury

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