Eccles, John (1903-1997)
ECCLES, JOHN (1903-1997)
The Australian-born scientist John Carew Eccles was a pioneer in neuroscience, discovering the elementary synaptic processes of the central nervous system known as excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs). He was particularly eager to understand how synaptic changes could serve learning and memory processes. He was awarded the Nobel Prize in physiology or medicine in 1963 for his pioneering analysis of central synaptic transmission.
Eccles was born on January 27,1903, in Melbourne, Australia. His parents, Mary and William Eccles, were both schoolteachers and strongly supported his academic interests. Although he was highly interested in mathematics, he eventually decided to study medicine and entered Melbourne University at the age of seventeen. After finishing his medical course with top marks in 1925, he won a Rhodes Scholarship and entered Magdalen College, Oxford, as an undergraduate. In 1927, he began working with Charles Sherrington, Nobelist and pioneer of neurophysiology. Together they discovered the dual-fiber composition of the ventral spinal nerve roots and established the time course of the central excitatory state and the contrasting central inhibitory state, excitability changes induced in spinal motoneurones by an impulse volley arriving from the same or the antagonistic muscle nerve, respectively. In 1929, Eccles received a D. Phil. degree from Oxford for a thesis on excitation and inhibition.
Eccles's Main Scientific Discovery
Eccles's major scientific achievement was the identification of the membrane potential changes underlying synaptic transmission in the central nervous system. These studies began at Oxford with analyses of simpler synaptic systems such as the cat nictitating membrane, the cervical sympathetic ganglia, and the neuromuscular junction and continued with spinal cord and supraspinal synapses. In 1937, Eccles moved to Sydney, where he set up a physiological laboratory in the Sydney Hospital and where he and W. J. O'Connor (1939) discovered and named the end-plate potential, the immediate electrical muscle cell response to the nerve impulse. In the early 1940s Eccles was joined by two distinguished scholars, Bernard Katz and Stephen Kuffler, who came to Australia as refugees fleeing Nazi Germany and Nazi occupation of Austria, respectively. Together they analyzed the properties of the end-plate potential (Eccles, Katz, and Kuffler, 1941, 1942), and Kuffler made his classical report on the effect of curare (Kuffler, 1942).
The Electrical-Chemical Synaptic Transmission Controversy
Between 1933 and 1938, Eccles made a set of studies on synaptic transmission through the cervical sympathetic ganglion and identified a fast and a slower type of transmission. A pharmacological analysis led him to conclude that, although the slower variety of synaptic transmissions were chemically mediated by acetylcholine (ACh), faster transmissions were likely to be electrically mediated. This interpretation challenged the view of Henry Dale and colleagues (1936), who had hypothetized that all phases were due to ACh. Dale won the 1936 Nobel Prize for the codiscovery with Otto Loewi of acetylcholine as transmitter in the nervous system. Although the scientific debate was intense and lasted for several years, it never damaged the lifelong friendship between Eccles and Dale. Prompted by his friend the philosopher Karl Popper, whom he first met in New Zealand in 1946, and influenced by his demand for testability of the ideas and with falsification as an admirable scientific goal, Eccles in 1949 restated his hypothesis that neuromuscular and autonomous synapses are operated chemically, but transmission in the central nervous system is likely to be electrically mediated.
Discovery of EPSPs and IPSPs in Motoneurones
The introduction of new technology allowed researchers (Fatt and Katz, 1951) to clarify the situation at the neuromuscular synapse, and the issue of the spinal cord mechanism was resolved when Eccles and two younger colleagues, Lawrence Brock and Jack Coombs, working at Otago University in Dunedin, New Zealand (where Eccles had moved in 1946), succeeded in impaling cat motoneurones with glass micropipettes and recording the transmembrane responses to stimulation of various nerves (Brock, Coombs, and Eccles, 1952). A cathode follower and amplifier designed by Coombs allowed the use of high-impedance electrodes that helped identify these processes and were fundamental to the researchers' success. When activating the afferent nerve, the motoneurone response was a depolarizing signal (see Figure 1), which Eccles called the excitatory postsynaptic potential (EPSP). Conversely, stimulation of a nerve from an antagonistic muscle inhibited the motoneuron, signaled by a hyperpolarizing response, the inhibitory postsynaptic potential (IPSP). Injection of ions via the impaling microelectrode showed that the IPSP depended upon the chloride and potassium ion gradients across the membrane. For these discoveries, Eccles was awarded the Nobel Prize in physiology or medicine for 1963, shared with Alan Hodgkin and Andrew Huxley.
In 1951, Eccles suddenly came to the conclusion that his former position regarding synaptic transmission in the spinal cord was untenable and that the situation was mediated by a chemical transmitter, just as at peripheral synapses. Two convincing observations resulted. First, there was invariably a distinct time delay between the arrival of the afferent nerve impulse and the onset of the postsynaptic response; the electrical hypothesis required simultaneity. Second, the polarity of responses at excitatory and inhibitory synapses was reversed in spite of similar presynaptic action potentials in the two cases. Eccles suggested that the EPSP and IPSP were mediated by two different chemical mediators. The new results were discussed in detail in the first five chapters of his Waynflete Lectures, The Neurophysiological Basis of Mind (1953), delivered at Magdalen College, Oxford, in 1952. (A further three chapters discussed synaptic plasticity, the cerebral cortex, learning, memory, and the mind-brain problem.)
During his term at Otago University, Eccles successfully reorganized and modernized the physiology and biochemistry program, but his teaching burden was considerable. In 1953, he accepted a newly established chair of physiology at the John Curtin School of Medical Research in Canberra, Australia, and there he proceeded to set up a modern and efficient neurophysiological laboratory. Joined by scientific colleagues from Australia and abroad, Eccles continued to use intracellular recording to analyze reflex circuits. He also made a set of significant discoveries on synaptic plasticity—for example, that posttetanic potentiation (PTP) is associated with an enhanced EPSP amplitude to a standard test stimulus and, with Arthur Buller and Rosamund Eccles (his daughter), that motoneuronal type controls motor unit contraction speed, a remarkable case of neuronal plasticity. In 1955 he was invited to give the Herter lectures at Johns Hopkins University, printed as The Physiology of Nerve Cells (1957), a small book that had tremendous influence.
Eccles and his colleagues analyzed a newly reported form of spinal inhibition reported by Frank and Fuortes in 1957 and found that it was due to reduced transmitter release from the presynaptic terminals of the test fibers, a finding they described as presynaptic inhibition. Their pharmacological analysis pointed to gamma-amino-butyric acid (GABA) as the mediating agent. In other collaborations, Eccles made a series of valuable discoveries about pre- and postsynaptic inhibition in the dorsal column nuclei, recurrent inhibition in the thalamus, hippocampal basket cell inhibition, and cerebellar organization. The largest impact of Eccles's studies of supraspinal neurons came from his work on the cerebellum, supported by the neurohistologist János Szentágothai of Budapest and by findings made by Masao Ito of Tokyo, who found that cerebellar Purkinje cells were monosynaptic inhibitory on target neurons in intracerebellar and vestibular nuclei. In the influential book Cerebellum as a Neuronal Machine (1967), Eccles, Ito, and Szentágothai characterized all neuronal elements and their properties and produced a detailed chart of the cerebellum and.
The Mind and the Brain
In the last chapter of The Neurophysiological Basis of Mind (1953), Eccles gave a first account, largely in pictorial form, of a possible site of interaction between the mind and the physical machinery of the brain, concentrating on models for perception and will in motor tasks. From his adolescence, Eccles had been strongly interested in the mind-brain problem, and he returned to the subject throughout his life, in particular after 1975. Although he met considerable opposition from other neuroscientists, he proposed a set of models for illustrating an interaction between the mind and cortical neuronal activity. His writings reveal him as a dualist, with ideas similar but not identical to those of René Descartes, maintaining that our mental processes are not identical to the associated physical nervous activity. He incessantly strived to improve and clarify his mind-brain proposals; above all, he wanted to design situations where a dualistic influence on the brain, a separate effect of the mind, could be experimentally tested. His book The Self and ItsBrain (1977), coauthored with Karl Popper, achieved a wide readership and considerable influence.
A Magnificent Leader
A major factor in Eccles's success was his ability as a team builder and a leader. He demanded much of his colleagues, but he was generous and rewarding to those who engaged themselves fully in the research. Although his enthusiasm and excitement were infectious, he insisted upon controlled experiments and repeatability of observations to avoid false results. His main ambition was to acquire insight in the problems and phenomena under investigation and not merely a description. He combined wide knowledge and a tremendous working capacity (more than 550 scientific articles) with a keen demand for further understanding, the whole coupled to a humility toward the magnitude of the challenge of understanding the brain.
Brock, L. G., Coombs, J. S., and Eccles, J. C. (1952). The nature of the monosynaptic excitatory and inhibitory processes in the spinal cord. Proceedings of the Royal Society of London, Series B, Biological Sciences 140, 170-176.
Coombs, J. S., Eccles, J. C., and Fatt, P. (1955a). Excitatory synaptic action in motoneurones. Journal of Physiology (London) 130, 374-395.
—— (1955b). The inhibitory suppression of reflex discharges from motoneurones. Journal of Physiology (London) 130, 396-413.
—— (1955c). The specific ionic conductances and the ionic movements across the motoneuronal membrane that produce the inhibitory post-synaptic potential. Journal of Physiology 130, 326-373.
Dale, H. H., Feldberg, W. and Vogt, M. (1936). Release of acetylcholine at voluntary motor nerve endings. Journal of Physiology (London) 86, 353-380.
Eccles, J. C. (1949). A review and restatement of the electrical hypotheses of synaptic excitatory and inhibitory action. Archives des sciences physiologiques (Paris) 3, 567-584.
—— (1953). The neurophysiological basis of mind: The principles of neurophysiology. Oxford: Clarendon Press.
—— (1957). The physiology of nerve cells. Baltimore: Johns Hopkins Press.
Eccles, J. C., Ito, M., and Szenthágothai, J. (1967). The cerebellum as a neuronal machine. Berlin: Springer.
Eccles, J. C., Katz, B., and Kuffler, S. W. (1941). Nature of the end-plate potential in curarized muscle. Journal of Neurophysiology 4, 362-387.
—— (1942). Effect of eserine on neuro-muscular transmission. Journal of Neurophysiology 5, 211-230.
Eccles, J. C., and O'Connor, W. J. (1939) Responses which nerve impulses evoke in mammalian striated muscle. Journal of Physiology (London) 97, 44-102.
Fatt, P., and Katz, B. (1951). An analysis of the end-plate potential recorded with an intracellular electrode. Journal of Physiology 115, 320-369.
Frank, K., and Fuortes, M. G. F. (1957). Presynaptic and postsynaptic inhibition of monosynaptic reflexes. Federeation Proceedings 16, 39-40.
Kuffler, S. W. (1942). Electrical potential changes at an isolated nerve-muscle junction. Journal of Neurophysiology 5, 18-26.
Popper, K. R., and Eccles, J. C. (1977) The self and its brain. Berlin: Springer.