Dale’s principle: what is it and what does it say about neurons?

A summary of this scientific approach to neurons, popular until the 1970s.

Dale's principle is a general rule that states that a neuron releases the same neurotransmitter or group of neurotransmitters in all its synaptic connections. But what is the truth of it, and has current neuroscience partially or totally disproved this principle?

In this article we explain what Dale's principle is and what its validity is today, what the phenomenon of cotransmission consists of and an example of it.

What is Dale's principle?

Dale's principle or Dale's law, named after the English physiologist Henry H. Dale, who was awarded the Nobel Prize in Physiology and Medicine in 1936 for his findings on the transmission of nerve impulses, states that a neuron releases the same neurotransmitter (or group of neurotransmitters) in all of its synaptic connections..

This principle was initially postulated with some ambiguity; some scientists, including John C. Eccles, interpreted it as follows: "neurons release the same group of neurotransmitters at all their synapses"; while others interpreted the original statement in this other way: "neurons release only one neurotransmitter at all their synapses".

As can be seen, there seemed to be two versions of Dale's principle that stated something similar, but with nuances. At that time, only two neurotransmitters were known: acetylcholine and noradrenaline (then believed to be adrenaline); and the possibility of a neuron releasing more than one at a single synapse was not considered at all.

The ambiguity resulting from Dale's original hypothesis caused some confusion about what the postulated principle meant. Ultimately, it was misunderstood as denying the possibility that a neuron could release more than one neurotransmitter.

However, it has now been proven that Dale's principle, i.e., the hypothesis that a neuron releases only one neurotransmitter at all its synapses, is false. It is an established scientific fact that many neurons release only one neurotransmitter at all their synapses. the scientific fact that many neurons release more than one chemical messenger, a phenomenon called cotransmission, cotransmissiona phenomenon called cotransmission, which we will discuss below.

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The phenomenon of cotransmission

For many years, the scientific community's understanding of the mechanisms of neurotransmission has been subject to Dale's law or principle, which, as we have commented, postulated that the concept that a neuron releases only one neurotransmitter. However, from the 1970s onwards, new lines of thought and research emerged that challenged these ideas.

The concept of cotransmission began to be used in the mid-1970s by, among other scientists, Geoffrey Burnstock. This concept introduces the idea that individual neurons, both in the central nervous system and in the peripheral system, contain and can release a large number and variety of substances that are capable of influencing target cells.

Cotransmission thus involves, the release of several types of neurotransmitters, neuromodulators and substances from a single neuron, allowing more complex effects to be exerted on postsynaptic receptors and thus generating more complex communication than in normal transmission.This allows more complex effects to be exerted on the postsynaptic receptors and, thus, to generate a more complex communication than that produced in normal transmission.

Today we know that, contrary to what Dale's principle postulated, it is not exceptional for neurons to release neurotransmitters in the company of other substances (cotransmitters), such as ATP (energy source and important neurotransmitter of the nervous system), nitric oxide or neuropeptides (tiny fast-acting proteins).

There are several examples of neuronal cotransmission. In the sympathetic nervous system, ATP is co-released with noradrenaline, and both neurotransmitters are cotransmitted.and both neurotransmitters exert their action through the activation of certain receptors, which end up being expressed in smooth Muscle cells. Thus, ATP participates in the contraction of these muscles.

In parasympathetic nerves, we can also find examples of cotransmission. Acetylcholine, vasoactive intestinal polypeptide (VIP), ATP and nitric oxide are cotransmitters synthesized and released by this type of nerves. For example, nitric oxide acts as the main mediator of neurogenic vasodilation in cerebral vessels, whereas VIP plays an essential role during neurogenic vasodilation in the pancreas.

Studying the mechanisms of cotransmission: Aplysia

Once Dale's principle was overcome, the study of the impact of cotransmission on the activity of a neuronal circuit has been analyzed in detail in invertebrate animal systems, such as that of the Aplysia. Using electrophysiological techniques, the functions of cotransmitters in physiologically identified neurons in well-defined neuronal circuits have been identified and determined.

The Aplysia feed-forward circuit has provided important insights into the functional role of cotransmission, and how cotransmitters such as cardioactive peptide and myomodulin are able to modulate muscle contractions evoked by evoked by another neurotransmitter such as acetylcholine, which is released by motor neurons on the muscles in charge of controlling the animal's feeding behavior.

Aplysia can generate two antagonistic feeding behaviors, namely ingestion and egestion. Repetitive stimulation of the CBI-2 interneuron would activate a central feeding pattern generator in the buccal ganglion, thereby progressively producing motor programs of food digestion.

Egestion would be activated by repetitive stimulation of the esophageal nerve, which induces a short-term potentiation of synaptic transmission between the B20 interneuron and the B8 motor neuron. B20 would have neurotransmitters such as GABA and dopamine as cotransmitters.

Dopamine in this case would act as a fast excitatory transmitterby exerting an effect on a receptor similar to 5-HT3. Gaba, on the other hand, would have no direct effect on these synapses, but could potentiate dopaminergic responses by acting on the GABA b receptor and subsequently activating protein kinase C.

The latter is an example where a "conventional" transmitter (such as GABA) would evoke a modulatory effect, and the "modulating" transmitter (dopamine) would exert a conventional effect. This effect of GABA is considered an example of intrinsic modulation by a co-transmitter, as it modulates the circuit to which it belongs.

Bibliographical references:

• Burnstock, G. (1976). Do some nerve cells release more than one transmitter?. Neuroscience, 1(4), 239-248.
• Osborne, N. N. (1979). Is Dale's principle valid? Trends in Neurosciences, 2, 73-75.
• Strata, P., & Harvey, R. (1999). Dale's principle. Brain research bulletin, 50(5-6), 349-350.
• Vilim, F. S., Cropper, E. C., Price, D. A., Kupfermann, I., & Weiss, K. R. (1996). Release of peptide cotransmitters in Aplysia: regulation and functional implications. Journal of Neuroscience, 16(24), 8105-8114.