If neurobiologist Jennifer Morgan is right, one of the secrets to discovering how to treat spinal cord injuries in humans may lie in the neurons of lampreys—small, primitive fish that look like eels and that have gotten a bad reputation in the Great Lakes region for being parasitic on trout and other native species.
“When a human has a spinal cord injury,” says Morgan, assistant professor in the Section of Molecular Cell and Developmental Biology, “that’s pretty much it, because regeneration doesn’t occur readily within the central nervous system of mammals. Lampreys, on the other hand, recover almost complete function after a total break in the spinal cord. They can swim normally within 10-12 weeks after paralysis.”
When a human spinal cord is injured, says Morgan, the problem is two-fold. First, when our axons—the nerve conduits that act as transmission lines for the brain’s messages—are severed, they don’t typically grow back across the lesion. Second, even when they are able to regenerate, they don’t necessarily re-connect in a way that allows for synaptic communication.
Most of the current research into spinal cord injury, says Morgan, is looking at the first part of the equation—how to encourage axons to regenerate. Her research, which is being funded by grants from the Paralyzed Veterans of America and the Morton Cure Paralysis Fund, looks at the next step.
“Axon regeneration is a requisite,” says Morgan. “You have to have it. But how much regeneration do you need, and once we get the axons to the right place, how do they make a synapse that can work again in a way that’s meaningful?”
Lampreys, it turns out, are an excellent model organism for answering these questions. Their locomotor network for swimming is a simplified version of the basic network that humans have for walking. Their genome has been sequenced. They recover almost complete function after spinal cord injuries that would leave mammals paralyzed. And, perhaps most significantly, some of the lamprey neurons that are likely involved in this recovery of locomotive function are extraordinarily large, making them accessible for imaging and physiological studies.
“There are about 20 of these giant neurons, in particular, that start in the brain and send input to the spinal cord,” she says. “It doesn’t take a fancy microscope to see them. We can count them, perturb them, observe them. The comparable neurons in a mammalian system are far too small to study in such detail.”
What Morgan’s found, so far, has been fascinating. Lampreys regenerate axons far better than humans do, but even so they’re only regenerating about half of the severed axons. The regenerated axons don’t extend as far through the nervous system as the old ones did. Most surprisingly, there are often fewer synapses patching the regenerated axons into the nervous system than there were with the old axons.
“How does that work?” says Morgan “How could you get normal function with shorter axons, fewer axons, fewer synapses?”
Morgan’s working hypothesis, which she’s in the process of testing in the lab, is that the lamprey’s nervous system has found a way, in the aftermath of injury, to strengthen each individual synapse on the regenerated axons. Each synapse may be capable of releasing more neurotransmitter—more information—with each distinct trigger.
“We predict that if each one is getting stronger,” says Morgan, “we should be able to measure it with electrophysiology.”
If her hypothesis is confirmed, it could have considerable implications for developing new treatments for spinal cord injury. Her lab has identified a gene, for instance, that seems to be associated with increased neurotransmitter release following a spinal cord injury, and they’re trying see if recovery is even faster when that gene is overexpressed (or if recovery is diminished when the gene’s knocked out).
“Everyone’s now assuming that what you have to do is get the axons to grow out and make a whole bunch of synapses that get to the right targets,” she says. “An alternative might involve sparse regeneration but stronger synapses.”
Morgan is careful to note that her work, even if it proves successful, is only a small part of the work that needs to be done before we’re anywhere close to meaningfully restoring function to victims of spinal cord injury. She’d be satisfied, however, just to contribute that small part.
“I’m just honored,” says Morgan, “to have gotten these grants from the Paralyzed Veterans of America and MCPF. They’re great organizations, and they’re incredibly serious about what they’re doing.”
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