The chicken or the egg question in a floppy infant syndrome: do motoneurons get sick before sensory neurons?

Which came first, the chicken or the egg? It is an old riddle that has puzzled countless generations.

Yet, scientists are now faced with another similar dilemma in Spinal Muscular Atrophy: which came first, sick motoneurons or sick sensory neurons?

Spinal Muscular Atrophy (SMA) affects 1 in every 6,000 newborns worldwide, making it the number one inherited cause of infant death ((Norrgard, K. (2008) Medical ethics: genetic testing and spinal muscular atrophy. Nature Education 1(1)).  Children with the most severe form of this genetic disease, Type I, typically live only until 14 months to 6 years of age ((Dubowitz, V. (1980). The Floppy Infant. )). These infants have a rag doll appearance, as their arms and legs hang by their sides accompanied by little or no head movement ((NINDS Hypotonia Information Page. (2013, March 15). )). Many of these affected children are also paralyzed for life, requiring extensive palliative care such as breathing and feeding aid. As a result, this is a devastating disease that exerts tremendous pain, both physical and psychological, on affected individuals and their families.

Currently there is no cure for SMA.

The disease is believed to be the clinical manifestation of unhealthy motoneurons, specialized cells in the spinal cord responsible for controlling muscle. Indeed, postmortem spinal cord tissues of SMA patients show evidence of extensive motoneuron dysfunction (Goran Simic). An effective cure of SMA will involve restoring health to these sick motoneurons. Since SMA results from deficiency of the Survival Motor Neuron (SMN) protein, putting SMN back in motoneurons is thought to be able to reverse motoneuron loss and therefore the disease.

However, this view has been challenged by recent reports from the Mentis and McCabe lab at Columbia University. In the nervous system, neurons often work with other types of neurons in interconnected neural circuits order to carry out highly-specialized roles. One such circuit is the sensory-motor circuit, involving sensory neurons, motoneurons, and interneurons. How the human body processes information can be simplified into inputs (information coming in) and outputs (what the body decides to do as a response). When there is an input (such as high temperature) from the outside environment, sensory neurons pick up that information and send it to the interneurons. The interneurons will then relay that information to motoneurons, which will activate in order to contract certain muscle (the output).

Sometimes, the sensory neurons will skip the interneuron middle man and connect directly onto motoneurons. When the Mentis lab at Columbia University studied this direct connection between sensory and motoneurons, they found major lapses in communication before there was motoneuron death in a mouse model of SMA ((MentisMentis, G., Blivis, D., Liu, W., Drobac, E., & Crowder, M. (2011). Early Functional Impairment of Sensory-Motor Connectivity in a Mouse Model of Spinal Muscular Atrophy. Neuron. )). Fewer connections were found between these cells, accompanied by the motoneuron's poor functional response to sensory neuron activation. When the connectivity impairments were fixed by pharmacological means, subsequent motoneuron loss was reversed. These findings were supported by a subsequent study by the McCabe lab, which utilized the fruit fly as a model. Contrary to the classical view that the motoneuron is the major therapeutic target for SMN up regulation, targeting the motoneurons yielded no rescue in a fruit fly model ((Imlach, W., Beck, E., Choi, B., Lotti, F., Pellizzoni, L., & McCabe, B. (2012). SMN is required for sensory-motor circuit function in Drosophila. Neuron.)). Unexpectedly, SMN must be increased in sensory neurons and interneurons in order to rescue motoneuron impairments.

“It was not clear whether the death of motor neurons is a cause of the disease or an effect," said Dr. McCabe, "Our findings in the fruit fly SMA model show that the disease originates in other motor circuit neurons, which then causes motor neurons to malfunction" ((Novel Mechanisms Underlying Major Childhood Neuromuscular Disease Identified. (2012, October 11).)). Essentially, the McCabe and Mentis studies suggest that SMA does not arise primarily from motoneurons. The motoneurons may even remain relatively healthy under conditions of low SMN, and thus motoneuron-specific expression of SMN will yield minimal benefit. Instead, the focus may be shifted to to sensory and interneurons, which are suggested to be the primary vulnerable neuronal populations that lead to secondary alterations in motoneurons.

Nothing in science ever comes through without some controversy and argument from the opposing side. To further investigate whether motoneuron dysfunction arose from within the cell or from external influences of other neurons in the motor circuit, the Didonato lab increased SMN in only motoneurons in SMA. Contrary to the McCabe study, motoneuron-specific expression of SMN was able to correct both motoneuron dysfunction and restored sensory-motor connectivity ((Gogliotti, R., Quinlan, K., Barlow, C., Heier, C., & Didonato, C. (2012). Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction. Journal of Neuroscience)). This study indicates that motoneuron dysfunction does indeed arise from the motoneuron itself, not from external influences as suggested by the McCabe and Mentis studies. In this case, the motoneuron may actually be influencing its external neurons, causing the sensory neurons and interneurons to become dysfunctional. If the motoneuron is a bad target for sensory and interneurons, then of course the strength of the sensory-motor connections will be weakened, which may explain why the Mentis study found the sensory-motor connections to be poor. By rescuing the motoneurons, sensory neurons now have a healthy target that facilitate stronger synaptic connections.

So we are faced with two contradicting studies. One shows that sick sensory neurons influence motoneurons. The other shows that sick motoneurons influence sensory neurons. Therein lies the chicken or the egg question in SMA: which came first, the sick motoneuron or the sick sensory neuron?

Figure. Two possible mechanisms behind SMA pathogenesis involving neurons in the motor circuit. A)  Primary defects originate from sensory neurons and interneurons, which then cause the motoneurons to malfunction. B)  Unhealthy motoneurons become bad targets for sensory neurons and interneurons. Thus, the motoneuron itself influences external neurons, leading to the malfunctioning of sensory neurons and interneurons. Figure made by Duy Phan, 2013.

Since SMA is a disease caused by low levels of the SMN protein, it is thought that restoring SMN levels in individuals would be a viable therapeutic option. Indeed, strategies to up regulate SMN have shown much promise in experimental mice data. However, an affective treatment will entail expressing SMN in the appropriate tissue that will yield the optimal benefit. In essence, we would like to ask the question where is SMN needed? On a fundamental biology level, answering the question will yield greater understanding about the SMN protein and its functions. On a clinical utility note, knowing the spatial requirement of SMN will guide us towards the correct therapeutic targets for SMA treatment.

Currently, two cell types are in question: is SMN needed in sensory neurons or in motoneurons? Due to the contradicting reports, much more study is needed to understand whether SMA is a motoneuron-autonomous or sensory neuron-autonomous disease. There is a great therapeutic urgency to elucidate the chicken or the egg conundrum in SMA.



From the author:

My goal as a neuroscience writer is to inspire. I want to inspire fellow high school students to take an interest in learning how the brain works, as the key to building the next generation of neuroscientists is to pass along my scientific passion. The easiest way to ignite curiosity is through reading and writing scientific papers. Why? Doing research isn't all about handling beakers and running reactions on the laboratory bench. Scientists do a tremendous amount of reading and writing, too. They read and write in order to understand what they don't know and identify new ideas for research. Similarly, reading and writing allow the high school students to explore the unknown without costs, providing every student with equal opportunity to learn about cutting edge science.
Neuroscience is very intimidating, and I get that. After all, how would any student learn to appreciate science if they are scared away? Moreover, I don't want to my articles to be too simple to the point where the science is gone. What's the point of reading a science article if there's no science? Thus, I wanted to combine the easy-to-understand writing style of Yahoo articles with the scientific rigor of PubMed articles. Through writing my review articles, I have learned to communicate complicated neuroscience concepts in a way that anyone could understand. When students begin to understand the science, they will see that neuroscience is very cool! I hope that my review articles will encourage students to become more curious about science.

-Duy Phan

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