Dale's principle: what it is and what it says about neurons

Dale's principle is a general rule which states that a neuron releases the same neurotransmitter or group of neurotransmitters at all of its synaptic connections. But what is true about it? Has current neuroscience, partially or totally, disproved this principle?

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

• Related article: "What are neurotransmitters and what function do they perform in our brain?"

What is Dale's principle?

Dale's principle or Dale's law, named after the English physiologist Henry H. Dale, 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) at 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 the norepinephrine (which at the time was believed to be adrenaline); and the possibility of a neuron releasing more than one at a single synapse was not considered at all.

The resulting ambiguity of Dale's original hypothesis led to some confusion about what the postulated principle meant. In short, it was misinterpreted as it was considered to deny the possibility that a neuron could release more than one neurotransmitter.

However, at present it has been possible to verify that Dale's principle, that is, the hypothesis that a neuron releases only one neurotransmitter in all its synapses, is false. It is established the scientific fact that many neurons release more than one chemical messenger, a phenomenon called cotransmission, which we will talk about next.

• You may be interested in: "What is the synaptic gap and how does it work?"

The phenomenon of cotransmission

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

The concept of cotransmission began to be used in the mid-70s by, among other scientists, Geoffrey Burnstock. This concept introduces the idea that individual neurons, both in the central nervous system and in the peripheral, contain and can release a large quantity and variety of substances that are capable of influencing cells aim.

Thus, cotransmission implies the release of various types of neurotransmitters, neuromodulators, and substances from a single neuron, allowing more complex effects to be exerted on postsynaptic receptors and, in this way, generating a more complex communication than that which occurs in normal transmission.

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

There are several examples of neural cotransmission. In the sympathetic nervous system, ATP is co-released with norepinephrine., and both neurotransmitters exert their action by activating certain receptors, which end up being expressed in smooth muscle cells. In this way, ATP participates in the contraction of these muscles.

In the 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 nerve. For example, nitric oxide acts as the main mediator of neurogenic vasodilation in blood vessels. brain cells, while VIP has an essential role during neurogenic vasodilation in the pancreas.

Studying cotransmission mechanisms: Aplysia

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

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

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

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 motor neuron B8. B20 would have neurotransmitters such as GABA and dopamine as cotransmitters.

Dopamine in this case would act as a fast excitatory transmitter, by exerting an effect on a receptor similar to 5-HT3. The gaba, for its part, would not have any direct effect on these synapses, but it could potentiate the 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 modulating effect, and the "modulatory" transmitter (dopamine) would exert a conventional effect. This effect of GABA is considered an example of intrinsic modulation by a cotransmitter, since it modulates the circuit to which it belongs.

Bibliographic references:

• Burnstock, G. (1976). Do some nerve cells release more than one transmitter? Neuroscience, 1(4), 239-248.
• Osborne, N. no. (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.