Dale's principle · Lobeworks/17

Dale's principle is the rule that a neuron releases the same neurotransmitter, or the same set of them, at all of its synapses; John Eccles gave it the name in 1954, after a lecture in which Henry Dale had argued in 1934 that a chemical released at one end of a neuron should be released at all its other ends.

Dale's principle. Dale's principle is the rule that a neuron releases the same neurotransmitter, or the same set of them, at all of its synapses; John Eccles gave it the name in 1954, after a lecture in which Henry Dale had argued in 1934 that a chemical released at one end of a neuron should be released at all its other ends.

The principle is about the sending side only. Whether a synapse excites or inhibits is decided on the receiving side, by the receptor that catches the transmitter: a channel that lets sodium or calcium in pushes the receiving cell toward its threshold, and one that lets chloride in or potassium out holds it down. So one transmitter can excite at one synapse and inhibit at another, and the label of a neuron as excitatory or inhibitory is a shorthand that holds when its targets all carry the same kind of receptor.

It lets a cell carry one label. Because the transmitter is the same at every terminal, a neuron can be typed by what it releases, which is how the fly's whole-brain models give each cell one sign.

In the fly the labels are rules of thumb. Acetylcholine excites, GABA inhibits, and glutamate, excitatory in most of the vertebrate brain, inhibits in the fly's olfactory system through a chloride channel, GluClα.

The transmitter itself is often inferred. In the fly connectome it was predicted for most cells by a network reading electron micrographs of their synapses, right for 94% of neurons.

It has exceptions. Many neurons release a fast transmitter together with a neuropeptide, and some release two fast transmitters; the principle survives in its broad form, the same set everywhere.

Questions: How does a connectome get the sign of each connection? Indirectly, in two steps. A network reads the transmitter from the electron micrograph of each synapse and pools the votes over the neuron, right for 94% of fly neurons; Dale's principle then lets the whole neuron carry that transmitter, and a rule turns it into a sign (acetylcholine positive, GABA and glutamate negative). Neither step is visible in the images as such, so the sign is a prediction stacked on an approximation. Does the transmitter or the receptor decide whether a synapse excites? The receptor decides. A transmitter is a messenger; the effect depends on the channel it opens on the receiving cell. If the channel lets sodium or calcium in, the cell moves toward its threshold; if it lets chloride in, the cell is held down. Glutamate is the standard example: it excites most vertebrate neurons through channels that pass cations, and in the fly's olfactory system it inhibits through GluClα, a channel that passes chloride. Why is glutamate inhibitory in parts of the fly brain? Because the receptor that catches it there is a chloride channel. Liu and Wilson showed in 2013 that glutamate hyperpolarises the main cell types of the fly antennal lobe and that the effect disappears when the glutamate-gated chloride channel GluClα is blocked or knocked down. Whole-brain fly models extend this to every glutamatergic neuron, which is a reasonable approximation that has been tested in particular circuits.