Neurons can adjust to changes in the body, but they never stop working unless there is a fatal injury. However, what signals neurons to keep acting and operating normally has long been a mystery.

Now, researchers at the University of Missouri (MU) say they have discovered that a neuron’s own electrical signal, or voltage, can indicate whether the neuron is functioning normally. If that voltage is absent, scientists say everything is “out of whack.”

“Our bodies have no central control system to tell individual neurons they are functioning normally, and so the neurons rely on their own electrical signals to keep track,” said David Schulz, PhD, a professor of biological sciences in the MU College of Arts and Science. “Without that electrical signal, the cell can’t tell if it is on the right track, and this can lead to changes that ultimately cause problems such as spasms and seizures. For people that have various neurological disorders, such as multiple sclerosis, epilepsy, and spinal cord injuries, this discovery could affect how they are treated to help reduce or eliminate such symptoms.”

The MU team’s study (“Membrane voltage is a direct feedback signal that influences correlated ion channel expression in neurons“), which appears in Current Biology, built on previous research by Schulz’s lab and involved examining neurons in crabs. Researchers completely shut down a crab’s nervous system and isolated neurons from their normal connections, activity, and chemical environment. Then, they artificially augmented the neurons’ reality.

“The number and type of ion channels present in the membrane determines the electrophysiological function of every neuron. In many species, stereotyped output of neurons often persists for years and ion channel dysregulation can change these properties to cause severe neurological disorders. Thus, a fundamental question is how do neurons coordinate channel expression to uphold their firing patterns over long timescales. One major hypothesis purports that neurons homeostatically regulate their ongoing activity through mechanisms that link membrane voltage to expression relationships among ion channels,” write the investigators.

“However, experimentally establishing this feedback loop for the control of expression relationships has been a challenge: manipulations that aim to test for voltage feedback invariably disrupt trophic signaling from synaptic transmission and neuromodulation in addition to activity.

Further, neuronal activity often relies critically on these chemical mediators, obscuring the contribution of voltage activity of the membrane per se in forming the channel relationships that determine neuronal output.

“To resolve this, we isolated an identifiable neuron in crustaceans and then either kept this neuron silent or used a long-term voltage clamp protocol to artificially maintain activity. We found that physiological voltage activity—independent of all known forms of synaptic and neuromodulatory feedback—maintains most channel mRNA relationships, while metabotropic influences may play a relatively smaller role. Thus, ion channel relationships likely needed to maintain neuronal identity are actively and continually regulated at least in part at the level of channel mRNAs through feedback by membrane voltage.”

“We fooled these isolated neurons into thinking they were acting normally by using a computer-driven process to produce their normal electrical signal,” Schulz said. “When we did this, there were very few changes in these cells, demonstrating that the cells thought it was ‘business as usual.’ It’s like providing an artificial generator when the power goes out while you are waiting for the power to be restored.”

The findings could inform future studies in people with spinal cord injuries, MS, and epilepsy. While there is no cure yet for spinal cord injuries, researchers believe this discovery could provide doctors with a way to trick neurons into thinking the body is still functioning normally. This would allow some level of normal nerve function to occur following the injury, and the affected nerves could re-join the healthy nerves above the injury.

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