Important discoveries often take advantage of the particularly favorable characteristics of an organ or organism. The discovery of the first neurotransmitter, acetylcholine, in the electrical organ of electric fish is a striking case.
In the second half of the 19 th century, the physiologist Claude Bernard studied curare mechanism of action. This fish of plant origin is used by Amazonian Indians to paralyze their prey with darts projected with blowguns. In 1878 he proposed that the curare prevent the contact between the nerves and the muscles by “poisoning” the nerve. E. Vulpian, his pupil, later showed that the curare blocked the communication between the nerves and the muscles.
The first one to have hypothesized the existence of a chemical messenger between the neurons is the Spanish Santiago Ramon y Cajal (1852-1934), one of the founders of neurosciences. On the basis of improved histological techniques, he described the neuron as the basic functional unit of the nervous system. Cajal was an artist of microscopic anatomy. For the record, Cajal, the son of a doctor, spent much of his youth observing and painting nature. He wanted to become a painter, but his father pushed him more towards medicine. He came to apply his great talent of fine observer and draftsman to the microscopy of the nervous system. Among others, he observed a space (synaptic cleft) between the neurons at their contact (synapse). Of the,
Representation of cerebral cortex neurons by Cajal
In studying the effects of the parasympathetic system, the English physiologist Dale (1914) observed that a chemical substance, acetylcholine (ACh), produced actions similar to this on the heart (slowing heart rate), but these effects Were of short duration. He deduced that the ACh reproduced the action of the parasympathetic nerves and that it had to be rapidly inactivated or destroyed. Then Loewi and Navratil (1921, 1926) carried out experiments, now classical, on stimulation of the vagus nerve (parasympathetic system), innervating an isolated heart of frog perfused with physiological serum. They observed a slowing of the heart rhythm due to the action of the vagus nerve. By placing the perfusion solution from this core in contact with a second isolated frog core, This second heart diminished the frequency of its beatings in turn. The first heart had released a substance, which they called Vagusstoff (vagal substance), capable of slowing down the second heart. Loewi later showed that the vagal substance was actually acetylcholine.
The work done by Dale and Loewi suggested that nerve transmission involves the release of acetylcholine from pre-synaptic nerve terminals and its interaction with receptors in the post-synaptic muscle membrane. This action was very rapid and difficult to determine because an enzyme, cholinesterase (Stedman et al., 1932) rapidly destroyed acetylcholine by hydrolyzing it to acetate and choline. However, they had not been able to show directly the release of acetylcholine.
At the Sorbonne, Nachmansohn and Marnay (1937, 1938) showed that the activity of cholinesterase in the frog muscles was greater in its innervated section than in its nerve-free portion. When the experiment was resumed in the electric organ of T orpedo marmata , Nachmansohn and Lederer (1939) found that the activity of cholinesterase was even higher in this organ than in the frog muscles. This high concentration of cholinesterase in a specialized organ suggested a certain function of acetylcholine in the generation of electric fish discharge.
Fessard, who studied the electrophysiology of Torpedo’s electrical organ , had shown that the discharge of the electrical organ was triggered by the release of a depolarizing substance from the terminals of the electromotive nerves, possibly acetylcholine.
Fessard invited Nachmansohn and Feldberg (from Cambridge at the time who had worked with Dale) to come to work at the University of Bordeaux at Arcachon. In the summer of 1939, they established that acetylcholine was responsible for the synaptic transmission to the electromotive synapses of Torpedo’s electrical organ (Feldberg, Fessard and Nachmansohn, 1939, Feldberg and Fessard, 1942). They based this interpretation on three scientific proofs. First, electrical organ extracts , under conditions that prevent the destruction of ACh, contain a substance that has the same effects as ACh on all systems tested (heart and abdominal frog muscle, dorsal leech muscle , Blood pressure of the cat, etc. ) And has the same chemical properties as ACh (sensitivity to cholinesterase and alkaline solutions). Second, ACh is released into the perfusates of the electrical organ stimulated by the nerves. Finally, arterial injection near the ACh electrical organ results in a discharge similar to that evoked by nerve stimulation.
Nachmansohn moved to the United States where he met Coates a passionate electric eel who worked at the New York Aquarium. Despite the Second World War raging, Coates managed to get supplies of electric eels. Nachmansohn, by studying the chemical reactions supplying energy for electrical conduction, discovered the enzyme choline transferase which synthesizes ACh from choline and acetyl-CoA. This enzyme is present in neurons releasing ACh. This research was funded by the US Department of War who was interested in the effects of DFP (di-isopropyl fluroophosphate), a neurotoxic gas that acts by blocking synaptic transmission. Nachmansohn showed that DFP inhibits the action of acetylcholinesterase.
As a medal has two sides, work on neurotransmitters, molecules released by neurons to synapses as chemical messengers, stimulated another area of research. If there is a chemical messenger released from one side of the synapse, there must be a receiver to accommodate it on the other side. After being published in 1900 by Paul Erlich, this theory of “key and lock” was taken up by Langley, who hypothesized that acetylcholine acted on the muscle because “there was a receptor” for ACh On the surface of muscle cells. Dale developed this theory of the receiver (1959) and Nachmansohn applied it to the receptors of ACh, then his students Karlin and Changeux took over.
Electric fish have always intrigued humans and have been part of the most challenging research that has allowed the invention of the electric battery, the discovery of nerve conduction, the discovery of synaptic transmission by a neurotransmitter. Even today, highly electric fish are used as a model for the study of synaptic transmission. For their part, weakly electric fish have become classical models in the understanding of sensory systems in neuroscience.
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