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Rescuing synaptic function may cure neuromuscular disease

Innovation is not always about using the latest and greatest scientific methods. Such is the case for Youfen Xu in her recent paper published in the Journal of Neuroscience. Youfen, working in Cynthia Jordan's lab, used a rather old fashion method--recording from muscle fibers--to listen in on how disease affects the function of neuromuscular synapses in three different mouse models of spinal bulbar muscular atrophy (SBMA), a late-onset neurodegenerative disease that robs men of the capacity to walk, run, chew, swallow, etc... While SBMA is not typically lethal--that is, life span is on average normal--quality of life is profoundly affected.  

What is innovative? The innovation in Youfen's study was challenging the current dogma: the assumption that motor dysfunction in SBMA is caused by degeneration of motoneurons.  While mouse models of SBMA show that motor dysfunction occurs without motoneuron death, the quest to identify new therapeutic targets for rescuing motoneurons from dying continues. Youfen hypothesized that if motor dysfunction is not caused by loss of motoneurons, then perhaps synaptic drive at the motoneuron-muscle interface fails. And indeed, this is what she found.

What was done? Using an ex vivo approach, Youfen stimulated the muscle's nerve and recorded electrical potentials from individual muscle fibers. Muscle contraction was blocked by ?-conotoxin, a muscle-specific sodium channel blocker. While Youfen set out to determine whether disease impairs synaptic function, she quickly discovered that the electrical properties of diseased muscle fibers were different: their resting potentials were closer to threshold for triggering contraction and ?-conotoxin did not effectively block their sodium channels, suggesting that sodium channels were somehow affected by disease. She also found that the kinetics of spontaneous and evoked synaptic potentials were affected, suggesting that the acetylcholine receptors (AChRs) were also perturbed. Furthermore, she learned that motor terminals at diseased junctions are uniformly weak, releasing 30-40% less neurotransmitter when stimulated. She went on to determine that the loss of synaptic strength is most likely caused by deficits in the probability of synaptic vesicle release and in the size of their readily releasable pool. Joined by Casey Henley and Kathy Halievski to better understand how the sodium channel and AChR was affected, they used qPCR to determine that disease induces the expression of the neonatal isoforms of these proteins. Remarkably, the physiology and gene expression defects were found in all three mouse models, making it likely that the discoveries made open up new and valid avenues for treating men with SBMA.

What may be going on in SBMA? Disease causes nerve terminals to become weak, and thus, less and less able to trigger action potentials in the fiber which in turn, leads to deficits in contraction. Perhaps in response to this loss in presynaptic strength, the muscles compensate, by moving their resting potential closer to threshold, making them easier to excite. Because inactivity can cause muscle fibers to revert to an immature state, it is possible that the return to expressing neonatal isoforms of key ion channels reflects a deficit in activation.  

What's next? Youfen will tackle the more difficult question of whether synaptic and/or muscle dysfunction actually underlies the loss in motor function. Preliminary data already tells her that much of the dysfunction found in end-stage mice is there in pre-symptomatic juvenile mice. Does this mean that synaptic and muscle dysfunction, while undoubtedly early signatures of disease, are necessary but not sufficient to disrupt motor function? A less satisfying but nonetheless viable alternative explanation is that muscle and synaptic dysfunction do not underlie the loss of motor function in SBMA.

Read the full article.

MSU Today Press Release

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