Dale's principle
Encyclopedia
In neuroscience
, Dale's Principle (or Dale's Law) is a rule attributed to the English neuroscientist Henry Hallett Dale
. The principle basically states that a neuron
performs the same chemical action at all of its synaptic
connections to other cells, regardless of the identity of the target cell. However, there has been disagreement about the precise wording.
Because of an ambiguity in the original statement, there are actually two versions of the principle, one that has been shown definitively to be false, and another that remains a valuable rule of thumb. The term "Dale's Principle" was first used by Sir John Eccles
in 1954, in a passage reading, "In conformity with Dale's principle (1934, 1952) that the same chemical transmitter
is released from all the synaptic terminals of a neurone…" Some modern writers have understood the principle to state that neurons release one and only one transmitter at all of their synapses. Others, including Eccles himself in later publications, have taken it to mean that neurons release the same set of transmitters at all of their synapses.
Dale himself never stated his "principle" in an explicit form. The source that Eccles referred to was a lecture published by Dale in 1934, called Pharmacology and nerve endings, describing some of the early research into the physiology of neurotransmission. At that time, only two chemical transmitters were known, acetylcholine
and noradrenaline
(then thought to be adrenaline
). In the peripheral nervous system, cholinergic and adrenergic transmission were known to arise from different groups of nerve fibers. Dale was interested in the possibility that a neuron releasing one of these chemicals in the periphery might also release the same chemical at central synapses. He wrote:
And near the end of the paper:
With only two transmitter chemicals known to exist at the time, the possibility of a neuron releasing more than one transmitter at a single synapse did not enter anybody's mind, and so no care was taken to frame hypotheses in a way that took this possibility into account. The resulting ambiguity in the initial statements led to some confusion in the literature about the precise meaning of the principle. Nicoll and Malenka, for example, understood it to state that a neuron always releases one and only one neurotransmitter at all of its synapses. In this form it is certainly false. Many neurons are capable of releasing more than one neurotransmitter, in what is called "cotransmission". The discovery of this phenomenon was relatively recent: although there were earlier hints, the first formal proposal did not come until 1976. Recent studies in a myriad of systems have shown that most, if not all, neurons release several different chemical messengers.
In a 1976 publication, however, Eccles reinterpreted the principle in a subtly different way:
The addition of "or substances" is critical. With this change, the principle allows for the possibility of neurons releasing more than one transmitter, and only asserts that the same set are released at all synapses. In this form, it continues to be an important rule of thumb, with only a few known exceptions., including David Sulzer
and Stephen Rayport's finding that dopamine neurons also release glutamate as a neurotransmitter, but at separate release sites. In modern neuroscience, neurons are often classified by their neurotransmitter and most important cotransmitter, for example striatal GABA neurons utilize either opioid peptide
s or substance P
as the primary cotransmitter.
Neurons in a class without a subpopulation of inhibitory interneurons can release at least two neurotransmitters at the same time, the other being a cotransmitter, in order to provide the stabilizing negative feedback required for meaningful encoding. Examples include:
Neuroscience
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. However, it is currently an interdisciplinary science that collaborates with other fields such as chemistry, computer science, engineering, linguistics, mathematics,...
, Dale's Principle (or Dale's Law) is a rule attributed to the English neuroscientist Henry Hallett Dale
Henry Hallett Dale
Sir Henry Hallett Dale, OM, GBE, PRS was an English pharmacologist and physiologist. For his study of acetylcholine as agent in the chemical transmission of nerve impulses he shared the 1936 Nobel Prize in Physiology or Medicine with Otto Loewi.-Biography:Henry Hallett Dale was born in Islington,...
. The principle basically states that a neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
performs the same chemical action at all of its synaptic
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
connections to other cells, regardless of the identity of the target cell. However, there has been disagreement about the precise wording.
Because of an ambiguity in the original statement, there are actually two versions of the principle, one that has been shown definitively to be false, and another that remains a valuable rule of thumb. The term "Dale's Principle" was first used by Sir John Eccles
John Carew Eccles
John Carew Eccles, AC FRS FRACP FRSNZ FAAS was an Australian neurophysiologist who won the 1963 Nobel Prize in Physiology or Medicine for his work on the synapse. He shared the prize with Andrew Huxley and Alan Lloyd Hodgkin....
in 1954, in a passage reading, "In conformity with Dale's principle (1934, 1952) that the same chemical transmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
is released from all the synaptic terminals of a neurone…" Some modern writers have understood the principle to state that neurons release one and only one transmitter at all of their synapses. Others, including Eccles himself in later publications, have taken it to mean that neurons release the same set of transmitters at all of their synapses.
Dale himself never stated his "principle" in an explicit form. The source that Eccles referred to was a lecture published by Dale in 1934, called Pharmacology and nerve endings, describing some of the early research into the physiology of neurotransmission. At that time, only two chemical transmitters were known, acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
and noradrenaline
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(then thought to be adrenaline
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
). In the peripheral nervous system, cholinergic and adrenergic transmission were known to arise from different groups of nerve fibers. Dale was interested in the possibility that a neuron releasing one of these chemicals in the periphery might also release the same chemical at central synapses. He wrote:
It is to be noted, further, that in the cases for which direct evidence is already available, the phenomena of regeneration appear to indicate that the nature of the chemical function, whether cholinergic or adrenergic, is characteristic for each particular neurone, and unchangeable.
And near the end of the paper:
When we are dealing with two different endings of the same sensory neurone, the one peripheral and concerned with vaso-dilatation and the other at a central synapse, can we suppose that-the discovery and identification of a chemical transmitter of axon-reflex vasodilatation would furnish a hint as to the nature of the transmission process at a central synapse? The possibility has at least some value as a stimulus to further experiment.
With only two transmitter chemicals known to exist at the time, the possibility of a neuron releasing more than one transmitter at a single synapse did not enter anybody's mind, and so no care was taken to frame hypotheses in a way that took this possibility into account. The resulting ambiguity in the initial statements led to some confusion in the literature about the precise meaning of the principle. Nicoll and Malenka, for example, understood it to state that a neuron always releases one and only one neurotransmitter at all of its synapses. In this form it is certainly false. Many neurons are capable of releasing more than one neurotransmitter, in what is called "cotransmission". The discovery of this phenomenon was relatively recent: although there were earlier hints, the first formal proposal did not come until 1976. Recent studies in a myriad of systems have shown that most, if not all, neurons release several different chemical messengers.
In a 1976 publication, however, Eccles reinterpreted the principle in a subtly different way:
"I proposed that Dale’s Principle be defined as stating that at all the axonal branches of a neurone, there was liberation of the same transmitter substance or substances."
The addition of "or substances" is critical. With this change, the principle allows for the possibility of neurons releasing more than one transmitter, and only asserts that the same set are released at all synapses. In this form, it continues to be an important rule of thumb, with only a few known exceptions., including David Sulzer
David Sulzer
David Sulzer is a American neuroscientist and Professor at Columbia University Medical Center in the Departments of Psychiatry, Neurology, and Pharmacology...
and Stephen Rayport's finding that dopamine neurons also release glutamate as a neurotransmitter, but at separate release sites. In modern neuroscience, neurons are often classified by their neurotransmitter and most important cotransmitter, for example striatal GABA neurons utilize either opioid peptide
Opioid peptide
Opioid peptides are short sequences of amino acids that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Opioid peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble opiates...
s or substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
as the primary cotransmitter.
Neurons in a class without a subpopulation of inhibitory interneurons can release at least two neurotransmitters at the same time, the other being a cotransmitter, in order to provide the stabilizing negative feedback required for meaningful encoding. Examples include:
- GABAGabâGabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
glycineGlycineGlycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
co-release. - DopamineDopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
glutamate co-release. - AcetylcholineAcetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
glutamate co-release. - AcetylcholineAcetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
(ACh) vasoactive intestinal peptideVasoactive intestinal peptideVasoactive intestinal peptide also known as the vasoactive intestinal polypeptide or VIP is a peptide hormone containing 29 amino acid residues that is produced in many tissues of vertebrates including the gut, pancreas and suprachiasmatic nuclei of the hypothalamus in the brain...
(VIP) co-release. - AcetylcholineAcetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
(ACh) calcitonin gene-related peptideCalcitonin gene-related peptideCalcitonin gene related peptide is a member of the calcitonin family of peptides, which in humans exists in two forms, α-CGRP and β-CGRP. α-CGRP is a 37-amino acid peptide and is formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11...
(CGRP) co-release. - Glutamate dynorphinDynorphinDynorphins are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 , multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neo-endorphin...
co-release (in HippocampusHippocampusThe hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
).