"The more we learn about
Schwann cells and the roles
glial cells play in the
periphery, we may find more
possibilities for clinical
Dr. Jane Lubischer
In 2002, these added up to significant opportunities for students and potentially important discoveries in the Department of Zoology in the College of Agriculture and Life Sciences.
Last Spring, Zoology 495N-Neurobiology, an introduction to studies of the nervous system from the molecular to the behavioral levels, was offered for the first time at N.C. State, taught by Dr. Jane Lubischer, assistant professor of zoology. Lubischer, who joined the department in Fall 2001, also is establishing a developmental neurobiology laboratory in the department.
There, Lubischer, who is slated to teach a course in cellular biology and conducts a graduate course in selected topics in neuroscience every fall semester, is conducting research in how the nervous system puts itself together during development and how it repairs itself after damage from injury or disease.
As her lab becomes complete, she and her students will be able to accelerate work in imaging the neuromuscular junctions in mice to explore certain theories and hypotheses about what happens on the cellular level when nerves are damaged. The labs in vivo imaging technology (microscopic images from a living animal) will enable her group to use fluorescent markers to tag different cells with different colors in anesthetized mice and observe the activities of those cells in response to partial denervation (removal of some of the neurons that innervate a muscle).
What they want to know is why adult neuromuscular systems adapt and repair themselves after partial denervation, while neonatal neuromuscular systems do not. Lubischer believes it has to do with the role of Schwann cells, the support cells of the peripheral nervous system (the system of nerves communicating signals between the central nervous system and the rest of the body).
Neurons and support cells (also called glial cells) are the two main classes of cells in the nervous system. Neurons are the functioning units of the nervous system that transmit signals between body locations, and they are made up of a cell body, axons and dendrites. Dendrites convey messages toward the cell body; axons convey messages from it as they branch into specialized endings called synaptic terminals. A synaptic terminal is where, for example, a message to move would be transmitted from brain to neuron to a target cell in a muscle.
Glial cells, such as Schwann cells, actually outnumber neurons and play important roles in the nervous system that are only recently being described, Lubischer explains. They were initially viewed as simply support cells for neurons, hence their name glia, which means glue.
The model system I study is the neuromuscular system, in which one neuron innervates each muscle fiber, Lubischer says. The site at which the neuron communicates with the muscle involves extensive branches formed by the neuron to release a signal and specialized receptors in the muscle fiber to receive that signal. The Schwann cells are also present, and they closely cover every branch of the neuron.
Other types of glial cells perform similar functions in the CNS, but Lubischers focus is on the Schwann cells, because, she says, one thing Schwann cells are good at is facilitating regrowth of neurons.
At least thats true in adult mice.
Weve been making the comparison between developing and mature systems in mice because there is a very dramatic change in the ability of the neuromuscular system to recover from injury, Lubischer explains.
In adults if you cut a nerve, it repairs itself. Similarly, after partial denervation of muscle removing some neurons, but not all remaining neurons would take over. In neonatal [14-day-old] mice, you cut a nerve and it will die. And after partial denervation in a neonatal mouse, the motor units [one motor neuron and all the muscle fibers it innervates] do not expand, she says.
We want to know why. What is the difference between adults and neonates in terms of this response to injury? If we understand that, we understand more about the system and whats truly critical for recovery from injury.
Recent studies from the University of Texas, where Lubischer conducted postdoctoral research, provided a clue: They showed sprouting taking place between innervated and denervated sites in adult animals.
Lubischer displays an image of a neurons axon leading to a patch of receptors on one muscle fiber. All the other receptors have been denervated. However, she points out that Schwann cells around the axon are extending to the receptors that have been denervated. Nerve cells are sprouting along the bridge formed by the Schwann cells between the innervated and denervated sites, suggesting that Schwann cells may encourage the sprout to grow there.
Thats in an adult animal. However, Lubischer says, findings from a neonatal animal show that Schwann cells die after denervation of the muscle.
The key point that Lubischer focuses on here is dead Schwann cells build no bridges. That reinforces her belief that the Schwann cell bridges in adult systems make the difference in signaling the sprouting from neurons to denervated muscle fibers.
Heres where my work starts, she says. To test this hypothesis, I first predicted a deficiency in terminal sprouting in neonatal motoneurons after partial denervation. What she found was that in neonatal mice there was no terminal sprouting triggered by partial denervation. But in adults 50 percent of the terminals grow sprouts just three days after the partial denervation.
Then she moved to the heart of the hypothesis that reactive Schwann cells in the nerve can support nodal sprouts. She found that neonatal neurons did sprout in areas where Schwann cells survived the partial denervation. Our conclusion was that motoneurons were perfectly capable of sprouting if they got the right signal. This work suggests that signal comes from the Schwann cells, she says.
However, says Lubischer, We also found something else we didnt expect in the neonatal animals.
The work described so far focused on the growth of sprouts by neurons that remained in the muscle after partial denervation and the failure to grow such sprouts in neonatal animals. The unexpected finding was that not only did neurons fail to grow sprouts after neonatal partial denervation, but the neurons seem to lose the terminal branches they had already formed. Not only were some branches gone, but the Schwann cells that would have covered those branches had also pulled back.
So the reason they are not compensating for the injury may be because they are losing the terminals they already have.
Therefore, she says, When the lab is complete, when we can do in vivo imaging, we want to study which goes first, the Schwann cells or the terminals.
Visualizing neuromuscular junctions in living mice requires a microscope that has the ability to image the in vivo animals muscle when anesthetized. Thats what the lab awaits, along with the computers and video cameras needed to put the system together, says Lubischer.
To get the lab up and running, a grant is pending, and start-up funds have just recently been made available.
Still, this lab-in-progress already has news to share.
The big-picture news is how important these glial cells are to nervous system function and regeneration, Lubischer says. Within the field, the news is that neonatal neurons may actually lose terminals after partial denervation. This raises questions about earlier research.
And, ongoing, the neurobiology courses and lab promise valuable opportunities to students, says Lubischer. Neuroscience is addressing important issues, spinal cord injuries, Alzheimers, Parkinsons, epilepsy. This neurobiology course gives the basics of the nervous system, tying in molecular and cellular bases of so many of the diseases and behavioral issues students should be aware of.
As for future practical
applications of this basic research, Lubischer says, It may come
back to spinal cord research. The more we learn about Schwann cells
and the roles glial cells play in the periphery, we may find more possibilities
for clinical applications. You do basic research, build a body of knowledge
and hope that some kind of treatment or cure will emerge.