Neurons and Synapses
The History of Its Discovery

Renato M.E. Sabbatini, PhD

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III. The Neuron Doctrine

In the same miraculous year of 1838 that Deiters and Remak published their landmark papers, two Germans, Mathias Jakob Schleiden (1804-1881), a botanist, and Theodor Schwann (1810-1882) (who had described for the first time the myelin sheath that covers some nerve fibers), proposed a more daring cell theory, i.e., that all organic tissues are composed of cells, and therefore, that the nervous system should be also so organized.

Advances in this area culminated with the so-called Neuron Doctrine, established as a result of the remarkable work done by Spanish anatomist Santiago Ramon y Cajal (1852-1934), on the basis of the histological techniques developed by Italian anatomist Camillo Golgi (1843-1926). Both received the 1906 Nobel Award in Medicine and Physiology.

Camillo Golgi was responsible for inventing a specific staining technique for neurons, which he called "the reazione nera" (the black reaction). It consisted in fixing silver chromate particles to the neurilemma (the neuron membrane) by reacting silver nitrate with potassium bichromate. This resulted in a stark black deposit on the soma as well as on the axon and all dendrites, providing a exceedingly clear and well contrasted picture of neuron against an yellow background (see picture below). For the first time, neuroanatomists could follow where the ramifications went in and out a particular spot in the nervous system, and describe with exquisite detail all the richness of these ramifications. A marvelous picture of complexity emerged, and Golgi was able to explore it in full, describing for the first time, for example, that axons also gave collaterals, which provided a divergence of connexion which was heretofore suspected of, but not proven.

Golgi defended the reticularist position, though, because he could not see with certainty that axons did not fuse to other cells. He wrote: “There is certainly to be found a very widespread network of filaments anastomosing one with the other throughout the gray matter of the brain.”

One of the reasons is that Golgi´s technique was unreliable, because it didn´t stain all neurons in a preparation, and was not effective with myelinated axons. Being unable to see a clear separation between the ramifications of adjacent neurons, Golgi was a staunch defender of the reticularist hypothesis, which he thought made more sense to understand the way the network operated. However, as we will see, there was mounting evidence that neurons were, indeed, individual cells which did not continue into each other by means of protoplasmatic fusion (protoplasm was a term coined by Purkinje). This evidence came from three sources:

• Improved histological techniques, which were pioneered by Santiago Ramón y Cajal, in Spain, beginning in 1887. Cajal improved the Golgi technique and also used younger brains and brains of birds, which have more abundant nonmyelinated axons. Cajal was a prodigious scientist, undoubtedly the greatest neuroanatomist of the 19th century, and his refined technique and extraordinary drawings of the neural tissue in the cortex, cerebellum, hippocampus, thalamus, spinal chord, and many other parts of the brain, convinced himself and many other scientists, as we will see later, that there was no evidence for the reticularist hypothesis. Everywhere in the nervous system he saw individual neurons. Particularly, basket endings of axons near cell bodies convinced Cajal that there was no continuity between axons and neurons
• Embryological evidence: Wilhelm His, as well as Cajal, documented in 1886 that the dendrites and axons growth out progressively in immature neurons observed in brains of embryos. Therefore, a hypothesis of contact between neurons is more probable than of anastomosis between neurons, because things that grow separately tend to stay so. His suggested that "we shall ultimately have to accommodate to the idea that the transmission of a stimulus without direct continuity is possible… ".
• Evidence of cell degeneration: Auguste-Henri Forel (1848-1931), a prominent Swiss scientist observed in the same year as His (1886), that when the neuron cell body dies or an axon is cut, degeneration in the remaining parts of the neuron stop at the junction to another neuron, thus giving evidence that they are separate. Otherwise, degeneration would spread unchecked to the whole network. Forel concluded that "...ultimately the branching always takes the shape of extensively ramified, interlocked trees, but anastomosing is found nowhere”

Cajal s Contributions

When Cajal started to work in the fine structure of the nervous system in 1888, using his modified Golgi technique, he was practically unknown to the rest of the world, mainly because he chose to publish in Spanish, in a journal founded and supported by him. He soon felt, however, that this isolation would keep his splendid work away from the eyes of those who really  mattered in neuroscience at that time, which were the Germans. So, he translated some of his papers to German and presented them in important international conferences in 1889. The sheer brilliance of his work and the audacity of his conclusions soon conquered many adepts, including two important ones: Rudolph Albert von Kölliker and Wilhelm von Waldeyer. Von Kölliker, who was a tenacious defender of the reticular hypothesis, converted to Cajal´s arguments for the independence of neurons and supported his cause. He even learned Spanish in order to translate Cajal´s works to German. Finally, Waldeyer wrote a tremendously influential review in 1891, putting reticularism to rest and spelling out the new neuronal doctrine. It was based on the conclusions of many researchers, such as Forel, His, and others, but Cajal s pathbreaking effort was evident everywhere.

A typical drawing made by Cajal (in this case a section of the spinal chord)
showing its superior technique and richness of detail

Particularly relevant were Cajal s conclusions about the way action currents propagate in neuronal networks, always in the direction of dendrites to axons, and there to the dendrites or soma of other neurons. He called this the Law of Dynamic Polarization , which was another fundamental contribution to neurophysiology.

 The neuronal doctrine had four tenets: 

• The neuron is the structural and functional unit of the nervous system;
• Neurons are individual cells, which are not continuous to other neurons, neither anatomically nor genetically;
• The neuron has three parts: dendrites, soma (cell body) and axon. The axon has several terminal arborizations, which make close contact to dendrites or the soma of other neurons;
• Conduction takes place in the direction from dendrites to soma, to the end arborizations of the axon

Among many other things, Cajal discovered characteristic structures in dendrites, which he called "spines" because of its appearance. Much later, these important structures were clarified to be part of the receptor apparatus of synapses in dendrites, and that they can change in number and morphology in response to function. Cajal was almost clairvoyant in proposing that the increase in the number of synapses could be one of the mechanisms of learning and memory, a fact that was ascertained only much later.

For their contributions, Golgi and Cajal shared the 1906 Nobel Prize. It is interesting to note that in his acceptance speech, Golgi chose to stubbornly defend  the reticularist hypothesis, even in the light of all previous evidence. Golgi was further mistaken by holding the view that dendrites did not participate in the communication, but had rather nutrition support functions for the neuron. He was immediately contradicted in all points by Cajal´s speech!

As a result of the extraordinary contributions of Cajal to science, he is ranked by historians at the same level of Copernicus, Vesalius, Galileo, Newton and Darwin

Neurons and Synapses: The History of Its Discovery By Renato M.E. Sabbatini, PhD Brain & Mind Magazine, 17, April-July 2003 Copyright 2003 Renato M.E. Sabbatini Part 3 of 6 Published on 23.Feb.2003