The ins and outs of the action potential are taught to every neuroscience undergraduate. Neurons, when excited, generate an action potential, which is propagated along the axon to the nerve terminal, where it causes the quantized release of neurochemical transmitters from vesicles into the synaptic cleft. The transmitter molecules diffuse across the synapse, binding to receptors on the post-synaptic cell and causing it too to generate an action potential.
It was taken for granted that the action potential is all or nothing. In other words, a neuron will only generate an electrical impulse if its membrane is polarized beyond a certain point (the ‘threshold’); otherwise, it will remain in its resting state.
Vertebrate neurons are therefore thought of as something like digital switches; they are either on or off, generating action potentials or resting. It was thought that the main determinant of neuronal activity was the frequency of electrical signals received by a cell.
Two recent studies, however, indicate that neurons may also use analogue signalling.
One study looked at mossy fibres in the hippocampus, the other at pyramidal cells in layer 5 of the cortex. Both show that the length over which a sub-threshold membrane event decays as it is propagated from its point of origin is much longer than was previously thought.
Shu et al demonstrate that 10mV depolarizations of the cell body membrane potential can increase transmitter release by up to 30%, probably because of spike broadening (a slower return to resting potential). In the experiments performed by Alle and Geiger, depolarizations of the cell body were shown to increase the amplitude of action potentials produced in the post-synaptic cell.
Physiologists have not, until now, noticed how these graded changes in membrane potential can affect neurotransmitter release. This is mainly because the electrical activity of neurons is usually investigated by using microelectrodes to take extracellular recordings, and this method does not record the sub-threshold fluctuations in membrane potential.
It is well known that invertebrate neurons can release neurotransmitters in response to minor changes in membrane potential. The threshold is however, much closer to resting potential in these cells than in the vertebrate neurons investigated in the current experiments.
These studies show that vertebrate neurons can function like those of 'lower' organisms. Furthermore, the vertebrate neurons in question are involved in the processing of information for complex functions such as memory and cognition. Could it be arrogance that led us to assume that vertebrate neurons function differently from invertebrate neurons?
The basics of brain function, which were thought to be well understood, are actually far more complex than was previously thought. Undoubtedly, there remains much more to be discovered. The mechanism of the action potential was discovered 50 years in a classic set of experiments by Hodgkin and Huxley, who used microelectrodes to measure the movements of electrical charge across the membrane of the giant squid axon in response to electrical stimulation.
Neurons have a low concentration of sodium ions and a high concentration of potassium ions with respect to the outside of the cell. In such a situation, ions tend to move down their concentration gradient (i.e. from an area of high to an area of low concentration). The nerve cell membrane prevents this diffusion, (although there is some leakage), and instead can precisely control the movement of ions in both directions. It is this controlled movement of ions across the nerve cell membrane that underlies the action potential.
In its resting state, a neuron is said to be polarized – that is, the inside of its membrane (the neurolemma) is negatively charged with respect to the outside, due to a high concentration of negatively-charged ions on the inside of the membrane. Textbooks usually give this ‘resting potential’ an average value of –70millivolts (9mV).
An action potential is initiated in response to the binding of neurochemical transmitter molecules to receptors on a nerve cell membrane. The consequent influx of positively-charged sodium ions lasts for approximately 1 millisecond and causes the membrane potential to move towards 0 mV (i.e. it is depolarizing).
When the voltage of the membrane peaks, the sodium channels close and potassium channels open. Because potassium is at a far higher concentration inside than outside the cell, the opening of the potassium channels causes potassium ions to flow out of the cell, repolarizing the cell (taking the membrane potential back towards it resting state). Potassium ion efflux actually causes the membrane potential to overshoot its resting value (i.e. hyperpolarization). The cell cannot generate more action potentials during this 'refractory period', but the membrane potential is very quickly brought back to its resting value.