Summary: Axon regeneration and dramatic improvements in functional recovery occurred when lactate was applied to damaged neural tissue. Treatment with lactate also significantly improved locomotion and restored some walking capability in mouse models of SCI.
Source: Temple University Health System
Dynamic networks that specialize in the transmission of information generally consist of multiple components, including not only primary processors, like computers, for example, but also numerous support applications and services. The human nervous system is fundamentally very similar–neurons, like computers, process and transmit information, sending molecular signals through axons to other neurons, all of which are supported by non-neuronal components, including an array of cells known as glia.
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 at the Lewis Katz School of Medicine at Temple University (LKSOM) and the University of Pennsylvania show that astrocytic glial cells can in fact play a major role in facilitating neuron repair.
“We found that glia have a metabolic switch associated with glucose metabolism that when triggered reverses inhibitory effects on growth and promotes axon regeneration,” explained Shuxin Li, MD, PhD, Professor of Anatomy and Cell Biology at Shriners Hospital’s Pediatric Research Center at LKSOM, and a senior investigator on the new study.
The research, published September 16 in the journal Cell Metabolism, is the first to establish a link between glucose metabolism in glial cells and functional regeneration of damaged neurons in the central nervous system.
In collaboration with senior investigator Yuanquan Song, PhD, Assistant Professor of Pathology and Laboratory Medicine at the University of Pennsylvania Perelman School of Medicine, Dr. Li and colleagues 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 what previous studies had indicated, 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,” Dr. Li said. “We also found that in injured mice, treatment with lactate significantly improved locomotor ability, restoring some walking capability, relative to untreated animals.”
Dr. Li and colleagues examined the specific pathway by which lactate and hydroxyglutarate act to enhance axon regeneration. 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,” Dr. Li said. “Moreover, this process is driven by a metabolic switch to aerobic glycolysis, which leads specifically to the production of lactate and other glucose metabolites.”
The researchers plan next to test the regenerative abilities of lactate and related molecules in larger animals and to determine which molecules are most effective for promoting regeneration. “The next phases of our work could set the stage for future translational studies in human patients affected by spinal cord injury,” Dr. Li added.
Other researchers contributing to the work include Feng Li and Jingyun Qiu, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia; Armin Sami, Harun N. Noristani, Kieran Slattery, Thomas Groves, and Shuo Wang, Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair) and the Department of Anatomy and Cell Biology, LKSOM; Kelly Veerasammy, Yuki X. Chen, Jorge Morales, and Ye He, The City College of New York; and Paula Haynes and Amita Sehgal, HHMI, Chronobiology and Sleep institute, Perelman School of Medicine, University of Pennsylvania.
Glial Metabolic Rewiring Promotes Axon Regeneration and Functional Recovery in the Central Nervous System
Highlights • Activation of the PI3K and EGFR pathways in glia promotes CNS axon regeneration • Enhanced glial glycolysis mediates the induced axon regeneration via metabolites • L-lactate and L-2HG are sufficient to boost CNS axon regeneration • The metabolites act on neuronal GABA B receptors to elevate cAMP as inverse agonists
Summary Axons in the mature central nervous system (CNS) fail to regenerate after axotomy, partly due to the inhibitory environment constituted by reactive glial cells producing astrocytic scars, chondroitin sulfate proteoglycans, and myelin debris. We investigated this inhibitory milieu, showing that it is reversible and depends on glial metabolic status. We show that glia can be reprogrammed to promote morphological and functional regeneration after CNS injury in Drosophila via increased glycolysis. This enhancement is mediated by the glia derived metabolites: L-lactate and L-2-hydroxyglutarate (L-2HG). Genetically/pharmacologically increasing or reducing their bioactivity promoted or impeded CNS axon regeneration. L-lactate and L-2HG from glia acted on neuronal metabotropic GABA B receptors to boost cAMP signaling. Local application of L-lactate to injured spinal cord promoted corticospinal tract axon regeneration, leading to behavioral recovery in adult mice. Our findings revealed a metabolic switch to circumvent the inhibition of glia while amplifying their beneficial effects for treating CNS injuries.