What Dale never said: multiple incarnations of Dale’s Law from the birth of pharmacology to modeling brain circuits

In the first half of the 20 th century, Sir Henry Dale played a major role in the development of modern pharmacology. Working with several newly identified biologically active substances and simple bioassays, Dale and his colleagues deduced the existence of specific transmitter and hormone receptors. They developed concepts of agonist and antagonist actions, many years before the receptor proteins responsible for the actions of neurotransmitters were purified and characterized. Dale observed that acetylcholine and epinephrine could evoke either excitatory or inhibitory actions on different target tissues, and postulated that these same substances were released in the central nervous system. This was turned by other scientists into the first instantiation of Dale’s Law, which stated that a given neuron only releases one neurotransmitter. In the second half of the 20 th century, it became clear that many neurons synthesize and release many cotransmitters that could elicit postsynaptic actions of variable signs and durations, and that the same neuron could be excitatory at some of its targets and inhibitory at others. Today, the theory community often uses the term “Dale’s Law” as a short-hand for models in which all of the postsynaptic actions of a modeled neuron are exclusively excitatory or inhibitory. While much can be learned from these models, this constraint should not be considered as a prerequisite for biologically realistic models. Doing so risks overlooking the open questions that have emerged through modern updates to Dale’s work.