Neurons are electrically charged cells in the nervous system that interpret and transmit information using electrical and chemical signals. A neuron’s electrical charge is determined by the flow of ions – charged atoms – in and out of the cell through pores, called ion channels. These pores open, allowing ions to rush in, and then shut. The neuron becomes charged and “sparks” the next neuron in line.
A new study from the lab of Dr. David Schulz in the Division of Biological Sciences provides the first biological evidence that neurons are finely “tuning” their own molecular-level machinery to regulate this flow of ions and thus their electrical charge.
The study, which appears as the cover article in the August issue of the scientific journal Current Biology, found that individual neurons are actively maintaining correlated levels of messenger RNA (mRNA) to ensure a consistent ratio of ion channels. mRNAs are molecules that carry instructions from genes to the protein-making machinery of the cell.
“We used to think that what determined a neuron’s electrical output was the fixed number of ion channels it has,” said David Schulz, associate professor in the Division of Biological Sciences in the College of Arts and Science and a researcher in the Interdisciplinary Neuroscience Program at MU. “Then came the important realization that the underlying amount of channels that generate an output can be totally different as long as it all balances out.”
In other words, the relative ratio of ion channels opening and closing, and not the underlying number, is important for generating each neuron’s spark. Thus, the activity of a neuron with 20 open channels and 30 closed channels is functionally the same as a neuron with 80 open channels and 120 closed channels.
“We previously discovered that this ratio is actively maintained at the protein level, at the level of these channels and the currents they generate, through direct feedback from the cell. So the question became how much of this extends down to the molecular biology – the DNA and RNA – of the neurons,” said Schulz.
Recent computational modeling studies had predicted that activity could directly regulate correlations in mRNA levels, but this had never been demonstrated in living biological neurons before. Schulz and his colleagues tested the hypothesis using a cluster of neurons called the stomatogastric ganglion that is at the center of a network of nerves and muscles that helps process food in the Jonah crab (Cancer borealis). Crabs and other invertebrates are useful in neuroscience research because their neurons are similar enough to our own that the research can be “scaled up” to apply to higher organisms, said Schulz.
Using a mix of molecular and electrophysiological approaches, Schulz and his colleagues established ion channel correlations in six different types of nerve cells, each with specific wave form outputs. From each cell type, they extracted and measured the amount of mRNA encoding each channel type. They found that the ratio of channel mRNA levels fit the ratio of channels used to produce each neuron’s output. This means the mechanism that keeps the channels in balance goes deeper than the channels themselves.
Furthermore, they found that the correlation between channel mRNAs disappeared following an interruption to the cell’s activity. This suggested to the scientists that the correlations were being actively maintained. To determine what form of feedback the nerve cells were using to maintain these correlations, the researchers completed a series of experiments designed to decouple the nerve cell’s electrical activity from the other possible neural changes.
“Long story short, when we finally got down to whittling it down it was really the actual voltage of the cell itself that is really the key factor that is constraining whether these correlations are there or not,” said Schulz. “The activity of the channels themselves triggers compensation events at the molecular level to control this crucial channel ratio.”
Schulz does not think nerve cells naturally experience a loss of activity or a loss of correlation and then somehow regain it. Rather, he said, nerve cells are constantly and very slightly “tuning” themselves to maintain a consistent electrical output.
“There is just this constant sort of check-in,” he said. “Activity change is detected, and it signals back to whatever is controlling the mRNA levels and saying, ‘hey, let’s make sure we’re keeping this on the right track.’”
Schulz said that these results represent a novel aspect of regulation that might be useful for developing therapeutics for neurological disorders later.
“Genetic mutations often found in neurological disorders create imbalances in the inward and outward flow of electrical current through cells,” said Schulz. “The variability in these imbalances, even between multiple cells of the same kind within the brain, is one of the major problems scientists face when trying to design therapeutics for disorders like epilepsy because seizures in individuals can be caused by different imbalances—therefore getting to the root of how neurons compensate for electrical changes makes our studies important.”
Notes about this neuroscience research
Coauthors of the study, “Activity-dependent feedback regulates correlated ion channel mRNA levels in single identified motor neurons,” include former graduate student Simone Temporal, Ph.D. 13, and current graduate student Kawasi Lett.