In Search of Memory: The Emergence of a New Science of Mind (14 page)

Eccles had every reason to be pleased, Popper argued. He urged Eccles to go back to the laboratory and refine his ideas and his experimental attack on electrical transmission even further so that he could, if necessary, actually disprove the idea of electrical transmission himself. Eccles later wrote about this encounter:

ECCLES DID NOT HAVE TO WAIT LONG FOR HIS HYPOTHESIS TO
be proved false. When Katz returned to University College, London, he provided direct evidence that the acetylcholine released by the motor neuron gives rise to and fully accounts for all phases of the synaptic potential. Acetylcholine does this by diffusing rapidly across the synaptic cleft and binding quickly to receptors on the muscle cell. Later, the acetylcholine receptor was shown to be a protein with two major components: an acetylcholine-binding component and an ion channel. When acetylcholine is recognized by and bound to the receptor, it causes the ion channel to open.

Katz went on to show that the novel ion channels gated by a chemical transmitter differ from voltage-gated sodium and potassium channels in two ways: they respond only to specific chemical transmitters, and they allow
both
sodium and potassium ions to flow through. The simultaneous passage of sodium and potassium ions changes the muscle cell’s resting membrane potential from-70 millivolts to nearly zero. Moreover, even though the synaptic potential is produced by a chemical, it is rapid, as Dale had predicted. When sufficiently large, it produces an action potential that causes the muscle fiber to contract (figure 6–2).

Together, the work of Hodgkin, Huxley, and Katz showed that there are two fundamentally different types of ion channels. Voltage-gated channels generate action potentials that carry information
within
neurons, while chemical transmitter-gated channels transmit information
between
neurons (or between neurons and muscle cells) by generating synaptic potentials in postsynaptic cells. Thus Katz discovered that by producing the synaptic potential, transmitter-gated ion channels in effect translate chemical signals from motor neurons into electrical signals in muscle cells.

Just as there are diseases of voltage-gated ion channels, so there are diseases of transmitter-gated channels. For instance, myasthenia gravis, a serious autoimmune disease that occurs primarily in men, produces antibodies that destroy the acetylcholine receptors in muscle cells and thus weaken muscle action. Muscular weakness can become so severe that patients cannot keep their eyes open.

SYNAPTIC TRANSMISSION IN THE SPINAL CORD AND BRAIN IS
decidedly more complex than signaling between motor neurons and muscle. Eccles had spent the years 1925 to 1935 working directly with Sherrington on the spinal cord. He returned to those studies full-time in 1945, and by 1951 had obtained intracellular recordings from motor neurons. Eccles confirmed Sherrington’s finding that motor neurons receive both excitatory and inhibitory signals and that these signals are produced by distinctive neurotransmitters acting on distinctive receptors. In the motor neuron, excitatory neurotransmitters released by the presynaptic neurons lower the resting membrane potential of the postsynaptic cell from–70 millivolts to–55 millivolts, the threshold for firing an action potential, while inhibitory neurotransmitters increase the membrane potential from–70 millivolts to–75 millivolts, making it much more difficult for the cell to fire an action potential.

6–2 The propagated action potential.

We now know that the major excitatory neurotransmitter in the brain is the amino acid glutamate, while the main inhibitory transmitter is the amino acid GABA (gamma-aminobutyric acid). A variety of tranquilizing drugs—benzodiazepines, barbiturates, alcohol, and general anesthetics—bind to GABA receptors and produce a calming effect on behavior by enhancing the receptors’ inhibitory function.

Eccles thus confirmed Katz’s finding that excitatory synaptic transmission is chemically mediated, and he showed that inhibitory synaptic transmission is also chemically mediated. When he described these findings in later years, Eccles wrote, “I had been encouraged by Karl Popper to make my hypothesis as precise as possible, so that it would call for experimental attack and falsification. It turned out that it was I who was to succeed in this falsification.” Eccles celebrated his discoveries by abandoning the electrical hypothesis he had so vigorously championed and converting wholeheartedly to the chemical hypothesis, arguing with equal enthusiasm and vigor for its universality.

It was at this point, in October 1954, that Paul Fatt, one of Katz’s outstanding collaborators, wrote a masterly review of synaptic transmission. Fatt took a farsighted view, pointing out that it was premature to conclude that all synaptic transmission is chemical. He concluded, “Although there is every indication that chemical transmission occurs across those junctions…which are most familiar to the physiologist,
it is probable that electrical transmission occurs at certain other junctions
[emphasis added].”

Three years later, Fatt’s prediction was convincingly demonstrated by Edwin Furshpan and David Potter, two postdoctoral fellows in Katz’s laboratory who found an actual case of electrical transmission between two cells of the nervous system in the crayfish. Thus, as sometimes happens in scientific controversies, both sides of the argument had merit. We now know that most synapses, including those under scrutiny at the time of the controversy, are chemical in nature. But some neurons form electrical synapses with other nerve cells. At such synapses there are small bridges between the two cells that allow electrical current to pass from one cell to the other, very much as Golgi had predicted.

The existence of two forms of synaptic transmission raised questions in my mind that would reemerge in my thinking later. Why do chemical synapses predominate in the brain? Do chemical and electrical transmission have different roles in behavior?

IN THE FINAL PHASE OF AN EXTRAORDINARY CAREER, KATZ
turned his attention from the synaptic potential in the target cell to the release of neurotransmitters from the signaling cell. He wanted to know how an electrical event in the presynaptic terminal, the action potential, leads to the release of a chemical transmitter. Here, he made two more remarkable discoveries. First, as an action potential propagates along the axon into the presynaptic terminal, it leads to the opening of voltage-gated channels that admit calcium ions. The influx of calcium ions into the presynaptic terminals sets off a series of molecular steps that lead to the release of the neurotransmitter. Thus, in the signaling cell, voltage-gated calcium channels opened by the action potential start the process of translating an electrical signal into a chemical signal, just as in the receiving cell, transmitter–gated channels translate chemical signals back into electrical signals.

Second, Katz discovered that transmitters such as acetylcholine are not released from the axon terminal as single molecules but in small, discrete packets containing about five thousand molecules each. Katz called these packets
quanta
and postulated that each one is packaged in a membrane-bound sac that he called the synaptic vesicle. In 1955, images of the synapse taken by Sanford Palay and George Palade with an electron microscope confirmed Katz’s prediction, showing that the presynaptic terminal is packed with vesicles that were later shown to contain neurotransmitters (figure 6–3).

6–3 How signals travel from cell to cell
. The first images of a synapse showed that the presynaptic terminal contains synaptic vesicles, which were later found to enclose about 5,000 molecules of neurotransmitter. These vesicles cluster near the membrane of the presynaptic terminal, where they prepare to release the transmitter into the space between the two cells, the synaptic cleft. After crossing the synaptic cleft, the neurotransmitters bind to receptors on dendrites of the postsynaptic cell. (Reprinted from
Cell
, vol. 10, 1993, page 2, Jessell and Kandel. Used with permission from Elsevier. Center image courtesy of C. Bailey and M. Chen.)

To test this idea further, Katz made a brilliant strategic decision. He shifted from studying the nerve-muscle synapse of the frog to the giant synapse of the squid. Using this advantageous system, Katz was able to infer what calcium ions do when they flow into the presynaptic terminal: they cause the synaptic vesicles to fuse with the surface membrane of the presynaptic terminal and open a pore in the membrane through which the vesicles release their transmitter into the synaptic cleft (figure 6–4).

THE REALIZATION THAT THE WORKINGS OF THE BRAIN—THE
ability not only to perceive, but to think, learn, and store information—may occur through chemical as well as electrical signals expanded the appeal of brain science from anatomists and electrophysiologists to biochemists. In addition, since biochemistry is a universal language of biology, synaptic transmission piqued the interest of the biological science community as a whole, not to mention students of behavior and mind, like me.

6–4 From electrical to chemical signals and back again
. Bernard Katz discovered that when an action potential enters a presynaptic terminal, it causes calcium channels to open, letting calcium ions flow into the cell. This leads to the release of neurotransmitters into the synaptic cleft. The neurotransmitter binds to receptors on the surface of the postsynaptic cell, and the chemical signals are reconverted into electrical signals.

How fortunate for brain science throughout the world that England, Australia, New Zealand, and the United States opened their doors to the remarkable scholars of the synapse cast out by Austria and Germany, including Loewi, Feldberg, Kuffler, and Katz. I am reminded of a story told about Sigmund Freud when he arrived in England and was shown the beautiful house on the outskirts of London that he was to live in. On seeing the tranquility and civility that his forced emigration had brought him to, he was moved to whisper with typical Viennese irony, “Heil Hitler!”