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Spinal Muscular Atrophy May Also Affect Sensory Neurons

For release: Thursday, June 2, 2011

Sensory-motor synapses in normal mice and SMA mice

Until recently, most researchers thought that problems with spinal muscular atrophy (SMA) began exclusively in motor neurons, the cells that transmit signals from the spinal cord to muscles telling them to move. But a new study, led by George Mentis, Ph.D., an investigator at Columbia University in New York City, may change that view. His results, published in Neuron,* suggest for the first time that SMA may also affect sensory neurons, the cells that transmit movements and sensations to the spinal cord.

“It changes the way we think about SMA”, said Kenneth Fischbeck, M.D., chief of the Neurogenetics Branch at the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland.

Occurring in about 1 out of every 10,000 births, SMA is the leading inherited cause of infant death in the U.S. The most severe form of the disease begins after birth by weakening the muscles that control movements in the torso, such as breathing, and then spreads outward, weakening more distant muscles in the limbs as a child grows. 

Muscle reflexes, such as the kick we make when a doctor taps our knees during a check-up, are primarily controlled by sensory and motor neurons. These neurons connect to each other in the spinal cord at sites called synapses (seen in the image above). The sensory neurons relay sensations, such as the tap, to the motor neurons. Upon receipt, the motor neurons relay the information back to the muscles, producing the kick.

SMA is caused by a genetic deficiency of a protein called survival motor neuron protein (SMN). As its name suggests, this protein is vital to motor neurons, and in SMA, a reduced level of the protein eventually leads to a catastrophic loss of motor neurons. Currently there are no cures for SMA. In animal studies, however, a few possible therapies have shown positive results, such as the compound Trichostatin A and the use of gene therapy to correct SMN levels.

The traditional thinking was that problems with SMA began in motor neurons and with the synaptic connections they make with muscles, called neuromuscular junctions (NMJ). However, previous studies by Charlotte Sumner, M.D., a neurologist at Johns Hopkins University in Baltimore, Maryland and a former post-doctoral fellow in Dr. Fischbeck’s lab, suggested otherwise. Her studies on mice genetically engineered to have SMA suggested that the disease causes only mild changes to NMJs.

“It is clear that problems at the NMJ have not provided the smoking gun”, said Dr. Fischbeck.

While working as a post-doctoral fellow in the laboratory of Michael O’Donovan, Ph.D., chief of the Developmental Neurobiology section at the NINDS, Dr. Mentis gave a talk at a weekly post-doctoral lecture series at NIH. The talk was about the development of sensory-motor neuron synapses, and afterward, he and Dr. Sumner began discussing whether those synapses might be affected by SMA.

To address the issue, Dr. Mentis first electrically recorded the strength of sensory-motor neuron synapses in spinal cord segments from SMA mice. He found that SMA mice had weaker connections than control mice and that the pattern of weakness matched the developmental pattern of muscle problems associated with the disease. Synapses that control torso muscles were weak immediately after birth whereas the synapses controlling limb muscles did not weaken until 2 weeks after birth. This was the first direct evidence suggesting that SMA causes problems with these synapses.

Next, Dr. Mentis used dyes and antibodies to visualize the synapses. These experiments revealed that SMA mice not only lost motor neurons over time but also lost the sensory neuron endings that connect to motor neurons. These losses progressed in a manner that could explain the disease. Moreover, in some spinal cord segments, the loss of the sensory neuron endings preceded motor neuron loss, suggesting the earliest problems associated with SMA may begin in sensory neurons.

Finally, the researchers tested whether Trichostatin A affected the sensory-motor neuron synapses of SMA mice. Previously, Dr. Sumner showed that giving SMA mice Trichostatin A improved their survival and muscle function without affecting NMJs.

In the new study, giving Trichostatin A strengthened the connections made by sensory-motor neuron synapses, and reduced the losses of motor neurons and sensory neuron endings, further supporting the idea that SMA may begin with these synapses.

“These results suggest that the synaptic connections onto motor neurons may be new targets for treatment of SMA”, said Dr. O’Donovan. As researchers test potential drug therapies in mice with SMA, looking at sensory-motor neuron synapses may provide them with a more complete picture of the drugs’ effects, he explained.

- By Christopher G. Thomas, Ph.D.

Image caption:  A comparison of normal and SMA mice reveaed that SMA mice experience an early loss of sensory-motor synapses (inside white dashed circles).  A red dye was used to fill sensory neurons, and antibodies (green spots) were used to detect a protein in sensory neuron endings.  Courtesy of Dr. George Mentis, Columbia University.

*Mentis GZ et al."Early Functional Impairment of Sensory-Motor Connectivity in a Mouse Model of Spinal Muscular Atrophy." Neuron, February 10, 2011, vol. 69, pp. 1-15.

Last Modified June 23, 2011