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 in all of its synaptic connections. But what is true about this? Have current neurosciences partially or completely refuted this principle?

In this article, we tell you what Dale’s Principle is and how valid it is today, what the phenomenon of co-transmission is and an example of it.

    What is Dale’s Principle?

    Dale’s Principle or Dale’s Law, named in honor of the English physiologist Henry H. Dale, who received the Nobel Prize in Physiology or 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, have interpreted it as follows: “neurons release the same group of neurotransmitters at all their synapses”; while others interpreted the original statement this way: “Neurons release only one neurotransmitter at all of its synapses.”

    As you can see, 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 norepinephrine (then believed to be adrenaline); and the possibility of a neuron releasing more than one at a single synapse has not been considered at all.

    The ambiguity resulting from Da’s original hypothesis caused some confusion as to the meaning of the postulated principle. Ultimately, it was misinterpreted as the possibility that a neuron could release more than one neurotransmitter was denied.

    However, it has now been proven that Dale’s Principle, i.e. the assumption that a neuron releases only one neurotransmitter at all of its synapses, is wrong. is established the scientific fact that many neurons release more than one chemical messenger, A phenomenon called cotransmission, which we will discuss below.

      The phenomenon of co-transmission

      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 discussed, postulated that the concept that a neuron releases only one neurotransmitter. However, from the 1970s, new lines of thought and research emerged that challenged these ideas.

      The concept of co-transmission 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 amount and variety of substances capable of influencing target cells.

      Co-transmission therefore implies the release of various types of neurotransmitters, neuromodulators and substances from a single neuron, Allowing to exert more complex effects on the postsynaptic receptors and, in this way, to generate a communication more complex than that which takes place in a normal transmission.

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

      There are several examples of neuronal co-transmission. In the sympathetic nervous system, ATP is huminated with norepinephrineAnd both neurotransmitters work 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, one can also find examples of co-transmission. 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 a major mediator of neurogenic vasodilation in brain vessels, while VIP plays an essential role in neurogenic vasodilation in the pancreas.

      Study of co-transmission mechanisms: Aplysia

      Having passed Dale’s principle, the study of the impact of co-transmission on the activity of a neural circuit has been extensively analyzed in invertebrate animal systems, such as that of Aplysia. Through the use of electrophysiological techniques, the functions of cotransmitters in physiologically identified neurons in well-defined neural circuits have been identified and determined.

      Aplysia’s feeding circuit provided important insight into the functional role of co-transmission and how cotransmitters such as cardioactive peptide and myomodulin they 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 feeding behavior of the animal.

      Aplysia can generate two antagonistic eating behaviors, namely: ingestion and digestion. Repeated stimulation of the CBI-2 interneuron would activate a central feeding pattern generator in the oral ganglion to thereby gradually produce motor food digestion programs.

      Eggestion would be activated by repetitive stimulation of the esophageal nerve, which induces a short-term potentiation of synaptic transmission between the interneuron B20 and the motor neuron B8. B20 is thought to be co-transmitted to neurotransmitters such as GABA and dopamine.

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

      The latter is an example in which a “classic” emitter (like GABA) would evoke a modulating effect, and the “modulating” emitter (dopamine) would exert a conventional effect. This effect of GABA is considered an example of intrinsic modulation by a cotransmitter, because it modulates the circuit to which it belongs.

      Bibliographical references:

      • Burnstock, G. (1976). Do some nerve cells release more than one transmitter ?. Neurosciences, 1 (4), 239-248.
      • Osborne, NN (1979). Is Dale’s Principle Valid? Trends in Neuroscience, 2, 73-75.
      • Strata, P. and Harvey, R. (1999). Dale’s Principles. Brain Research Bulletin, 50 (5-6), 349-350.
      • Vilim, FS, Cropper, EC, Price, DA, Kupfermann, I., and Weiss, KR (1996). Release of peptide cotransmitters in Aplysia: regulation and functional implications. Journal of Neuroscience, 16 (24), 8105-8114.

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