Research Brief: Mojo for Motor Neurons

Two recent papers suggest novel methods for treating paralysis in rodent models. One uses motor neuron grafts to improve function in mouse models of spinal muscular atrophy with respiratory distress type 1 (SMARD1)—a motor neuron disease that strikes in infancy. The other uses a combination of electrical stimulation and neurotransmitter agonists to induce oscillating neuronal activity in the spinal cord. Remarkably, that neural activity can generate coordinated motor outputs that enable adult rats to walk even though their spinal cords have been completely severed. Though neither method is ready for prime time, they demonstrate the breadth and depth of research that could lead to cures for a variety of motor neuron diseases.

SMARD is caused by a mutation in the gene that encodes Ig micro-binding domain protein 2 (IGHMBP2). The exact function of this protein is unknown, but the mutation causes motor neuron damage and eventually leads to muscular atrophy and paralysis of the diaphragm, causing respiratory failure. There is no cure. One experimental approach for motor neuron disease in general is to transplant embryonic stem (ES) cells or ES cell-derived motor neurons into the spinal cord of affected animals (see Deshpande et al., 2006). Researchers led by Giacomo Comi at the University of Milan, Italy, previously showed that a specific type of neural stem cell can delay disease progression and increase lifespan of the neuromuscular degeneration (nmd) mouse, which has an IGHMBP2 mutation. In the September 23 Journal of Neuroscience, this group reports similar improvements by transplanting motor neurons into the animals’ spinal cords.

Lead author Stefania Corti and colleagues purified motor neurons cultured from neural stem cells and then injected them into the spinal cords of 14-day-old nmd mice. Some of the mice also got a bonus—the motor neurons were first treated with dbcAMP, which promotes neural survival and axon outgrowth, and the animals were given rolipram and GDNF to overcome the inhibitory effect of myelin and to promote axon extension, respectively—the GDNF was injected into limb muscles to attract new axons. Five weeks later, treated nmd mice performed significantly better than untreated nmd controls on the rotarod, a test of muscle strength. At eight weeks, treated mice performed even better, suggesting that the cell grafts led to a gradual improvement. Mice receiving the bonus drug treatment performed slightly better than those receiving just the motor neurons. Both treatments improved weight gain and significantly extended lifespan, the scientists claim.

The treatment may have been successful for two reasons. Corti and colleagues found that transplanted neurons survived in the spinal cord and extended axons into numerous muscles, including the biceps, triceps, and quadriceps. Retrograde labeling revealed that the axons made contact at neuromuscular junctions in those muscles. Secondly, the transplants seemed to protect endogenous neurons, perhaps by reducing inflammation—elevation of pro-inflammatory cytokines such as interleukin 1β and chemoattractant proteins was substantially reduced in the treated mice. Whether this type of treatment will eventually prove successful for human SMARD or motor neuron diseases such as ALS remains to be seen, but it is an area of intense research.

The second approach to relieving paralysis is based on the concept of central pattern generators (CPGs). These are networks of neurons in the spinal cord that have the intrinsic ability to oscillate. Researchers led by Gregoire Courtine at the University of Zurich, Switzerland, tested if CPGs could be coaxed to generate stepping action in rats lacking brain input into the spinal cord. In the September 20 Nature Neuroscience online, the researchers report that a combination of epidural electrical stimulation (EES) at lumbar and sacral regions, together with drug treatment (using the 5-hydroxytryptamine 2A receptor agonist quipazine and the 5-HT1/5-HT7 receptor agonist 8-OHDPAT), activated spinal circuits and improved stepping motions of the hind legs in rats with severed spinal cords. The treatment also doubled the rats’ ability to bear weight. Next, the researchers used a treadmill (as is frequently used in rehabilitation from spinal cord injuries) to improve performance further. (Such locomotor training is known to promote improvement in walking after spinal cord injury—see Cote et al., 2004.) Rats receiving the full combination of EES, agonists, and rehab recovered full weight-bearing capability and had limb movements that were nearly identical to those recorded prior to spinal injury, the scientists report. This is an improvement over other similar attempts that achieved limited weight-bearing ability and resulted in abnormal kinematics or motion. “Our results indicate that the mammalian lumbosacral spinal cord contains circuitry that is sufficient to generate close-to-normal hindlimb locomotor patterns in the absence of any supraspinal input,” write the authors. See related movie below of treated animals.

Whether a similar approach could one day be used to stimulate stepping in paralyzed humans remains to be seen. For one thing, the authors note that more studies are needed to identify the location and types of neurons that are involved in the process. But there is evidence that the approach might prove useful to some people eventually. Following partial spinal cord injury (SCI), electrical stimulation has helped people walk again (see Carhart et al., 2004). Our findings “provide a conceptual framework for the design of strategies to ameliorate motor function in humans after SCI or in the context of other neuromotor disorders such as Parkinson’s disease,” write the authors. However, this particular approach would not be useful for people with ALS or other motor neuron diseases. “Our interventions critically depend on the integrity of motoneurons and spinal neuronal networks in general,” Courtine told ARF via e-mail. “It therefore has no relevance to motor neuron diseases.”—Tom Fagan

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References

Paper Citations

  1. Deshpande DM, Kim YS, Martinez T, Carmen J, Dike S, Shats I, Rubin LL, Drummond J, Krishnan C, Hoke A, Maragakis N, Shefner J, Rothstein JD, Kerr DA. Recovery from paralysis in adult rats using embryonic stem cells. Ann Neurol. 2006 Jul;60(1):32-44. PubMed.
  2. Côté MP, Gossard JP. Step training-dependent plasticity in spinal cutaneous pathways. J Neurosci. 2004 Dec 15;24(50):11317-27. PubMed.
  3. Carhart MR, He J, Herman R, D'Luzansky S, Willis WT. Epidural spinal-cord stimulation facilitates recovery of functional walking following incomplete spinal-cord injury. IEEE Trans Neural Syst Rehabil Eng. 2004 Mar;12(1):32-42. PubMed.

Further Reading

Primary Papers

  1. Corti S, Nizzardo M, Nardini M, Donadoni C, Salani S, Del Bo R, Papadimitriou D, Locatelli F, Mezzina N, Gianni F, Bresolin N, Comi GP. Motoneuron transplantation rescues the phenotype of SMARD1 (spinal muscular atrophy with respiratory distress type 1). J Neurosci. 2009 Sep 23;29(38):11761-71. PubMed.
  2. Courtine G, Gerasimenko Y, van den Brand R, Yew A, Musienko P, Zhong H, Song B, Ao Y, Ichiyama RM, Lavrov I, Roy RR, Sofroniew MV, Edgerton VR. Transformation of nonfunctional spinal circuits into functional states after the loss of brain input. Nat Neurosci. 2009 Oct;12(10):1333-42. PubMed.

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