Faster than theory allows
Neurobiologists have known for half a century: nerve cells transmit messages via action potentials, with sodium channels playing a crucial role. But the Hodgkin-Huxley model, named after its discoverers, may only be half the story.
Every living cell maintains an electrical potential difference across its cell membrane. Nerve cells distinguish themselves from other cells in that they use this voltage difference to process and forward messages. If a nerve cell receives a strong stimulus, the electrical voltage across the cell membrane reverses. This action potential propagates at high speed along the long processes of the cell, at the end of which the signal is transmitted to other nerve cells.
In 1952, Alan Lloyd Hodgkin and Andrew Fielding Huxley described how such an action potential arises using a mathematical model based on measurements on squid neurons. The Hodgkin-Huxley model, for which the scientists were later awarded the Nobel Prize, has since been used to explain signaling processes in all neurons.
According to the Hodgkin-Huxley model, an action potential is triggered when the electrical potential across the nerve cell membrane changes to a certain threshold value. Certain sodium channels respond to this change in voltage, opening up and triggering an avalanche-like response. Positively charged sodium ions flow into the cell through the opened channels, which leads to a further shift in the membrane potential and the opening of further sodium channels. The threshold and also the speed with which an action potential is generated vary from cell to cell - for an individual cell, however, these parameters are largely determined by the properties of its sodium channels.
An interdisciplinary team of physicists and neurophysiologists from the Max Planck Institute for Dynamics and Self-Organization in Göttingen and the Ruhr University Bochum has now examined the speed and the threshold value of action potentials in nerve cells of the cerebral cortex of the mammalian brain in more detail. In doing so, Björn Naundorf, Fred Wolf and Maxim Volgushev discovered that action potentials set in very erratically: although a single action potential lasts a good millisecond, a strong influx of sodium begins in the first 200 microseconds. The sodium channels seem to open almost simultaneously, so that sodium ions can flow into the cell very quickly and in large quantities. At the same time, however, the researchers found in their measurements that the threshold values at which the action potentials set in are very variable.
To understand why this unusual behavior comes about, the scientists first tried to reproduce the behavior of the cells in computer simulations of the Hodgkin-Huxley model. To their surprise, it turned out that a high variability in the threshold value and a sudden increase in the action potential cannot be combined within the framework of this model. The two properties behave in the model like the two sides of a seesaw. Assuming a high variability in the threshold value, the model requires a low rate of action potential onset. If high speed is required, the variability of the threshold is low.
In order to be able to reproduce the observed behavior of the nerve cells in computer simulations, the researchers postulated a new mechanism that explains how sodium channels do not always open at the same threshold value, but nevertheless almost synchronously. According to the new model, if a sodium channel opens, this affects other sodium channels in the immediate vicinity: the channels open "cooperatively" and not - as according to Hodgkin-Huxley - independently of one another and solely as a function of the voltage across the membrane.
To test this hypothesis, the scientists used a trick: If the cooperative mechanism could be measurably prevented, that would be a good argument for its existence. They achieved this by blocking part of the sodium channels with the neurotoxin tetrodoxin, so that the channels that were still functional were scattered widely in the membrane and could no longer cooperate. As expected, the action potentials observed in such experiments exhibited much slower dynamics.
In further investigations, the researchers were able to show that the cells probably use this novel mechanism to differentiate between the received signals and only respond to certain ones. "The cells work like a high-pass filter," says Naundorf, summarizing the results of these studies. "Fast signals are transmitted well, slow signals are suppressed."
The two aspects of action potential initiation play different roles. The large variability of the threshold potentials enables the cells to ignore slow-onset stimuli. They then continuously increase their threshold, so that in many cases no impulse is triggered at all. The rapid triggering of action potentials, on the other hand, helps the cells to pass on rapidly changing signals with great precision. According to the Hodgkin-Huxley model, however, they would not be able to do this.
"Many scientists - including us - no longer regarded the Hodgkin-Huxley model as a hypothesis, but believed that it can in principle be applied to all neurons," emphasizes Wolf. He and his colleagues have now shown that this is not the case. According to their results, the better brain performance of higher animals, such as cats or humans, compared to squid or snails, is not only due to the higher number of neurons in the brains of these animals, but also to the way in which the neurons work process signals. Presumably, they use molecular mechanisms that are not available to lower animals. © Max Planck Society
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