COLUMBUS, Ohio -- Researchers here in collaboration with a group in California have discovered that a protein normally thought only to be a component in the immune system actually plays a key role in regulating neurotransmission in the central nervous system -- the CNS -- as well.

The protein, tumor necrosis factor alpha, or TNF-alpha, has long been known to be a key player in controlling cell death but this new finding offers new insights into how cells interact within the human nervous system.

Understanding this new role of TNF-alpha may provide researchers with possible new approaches to treating illnesses such as dementia, Alzheimer's disease, stroke, epilepsy and spinal cord injury. The report was published in the latest issue of the journal Science.

The findings by Jacqueline Bresnahan, professor of neurosciences at Ohio State University; Michael Beattie, professor and chair of the same department, and colleagues at Stanford University, show that TNF-alpha is vital for controlling the strength of signal transmission between nerve cells. And the level of signal strength may play an important role in determining how nerve cells respond to injury.

Researchers have long believed that neurons were the most important cells in the nervous system because they controlled the passage of signals throughout the CNS. They thought that glial cells -- astrocytes, oligodendrocytes and microglia -- only performed a support role for those neurons, providing oxygen and nutrients to the neurons, shielding neurons from each other, and basically cleaning up dead neurons.

The new research, however, points to a much greater role for the glial cells since they can manufacture and release TNF-alpha into the CNS environment. The TNF-alpha apparently is able to regulate the expression of certain neurotransmitter receptors on the surface of neurons. The more of these receptors there are on the surface of the neuron, the more signals it can transmit.

In this case, the signals arise from the binding of glutamate molecules from the fluid surrounding the cell to these receptors. When the glutamate and receptor meet, a nerve impulse, or signal, is produced. The more receptors present, the more signals are increased.

Normally, the cytokine TNF-alpha is released as part of the inflammatory process following an injury to the cells. Based on discussions with other Ohio State colleagues on how the brainstem sends "nausea signals" to the stomach, Beattie and Bresnahan remembered that when TNF-alpha and glutamate are both present, cell signaling activity seemed to increase.

"We wondered that since there was glutamate and TNF-alpha present in the spinal cord after injury, then maybe TNF-alpha is actually enhancing the killing effect of the normal neurotransmitter," Beattie said.

In testing this, they exposed nerve cells first to glutamate and then to TNF-alpha. Separately, neither had an impact on the normal killing effect. But when they exposed the cells to even small amounts of both compounds, the killing effect increased 120 percent.

"This was a complete surprise and validated our hypothesis," Bresnahan said.

The real question, however, was in the details of the process -- how exactly was the killing effect enhanced. For help with the answer, they turned to Beattie's brother Eric, a post-doctoral researcher at Stanford. The lab in which Eric Beattie was conducting research was looking at the role glutamate played in signal transmission in learning and memory.

"We wanted to know if TNF-alpha was regulating the number of receptors on the cell surface," Bresnahan explained. "If the number of receptors increased, and if there was glutamate nearby to bind to them, that would allow more calcium into the cells, killing them."

Experiments at the Stanford lab were able to show that controlling the presence or activity of TNF-alpha had a direct relationship to the numbers of glutamate receptors on the cell surface and therefore on the amount of synaptic transmission.

"This showed that TNF-alpha, this cytokine that is supposed to come from the immune system and not have a role in transmitting information, is actually a potent modulator of neurotransmitter interaction," Beattie said.

Beattie and Bresnahan's work has now turned to how this process affects the speed at which nerve cells die, adding that a host of illnesses are caused by a degeneration of neurons.

Their work was supported by grants from the National Institutes of Health.

---American Neurological Association

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