Elsevier

Progress in Neurobiology

Volume 78, Issues 3–5, February–April 2006, Pages 189-214
Progress in Neurobiology

John Eccles’ studies of spinal cord presynaptic inhibition

https://doi.org/10.1016/j.pneurobio.2006.02.007Get rights and content

Abstract

Presynaptic inhibition is one of many areas of neurophysiology in which Sir John Eccles did pioneering work. Frank and Fuortes first described presynaptic inhibition in 1957. Subsequently, Eccles and his colleagues characterized the process more fully and showed its relationship to primary afferent depolarization. Eccles’ studies emphasized presynaptic inhibition of the group Ia monosynaptic reflex pathway but also included group Ib, II and cutaneous afferent pathways, and the dorsal column nuclei. Presynaptic inhibition of the group Ia afferent pathway was demonstrated by depression of monosynaptic excitatory postsynaptic potentials and inhibition of monosynaptic reflex discharges. Primary afferent depolarization was investigated by recordings of dorsal root potentials, dorsal root reflexes, cord dorsum and spinal cord field potentials, and tests of the excitability of primary afferent terminals. Primary afferent depolarization was proposed to result in presynaptic inhibition by reducing the amplitude of the action potential as it invades presynaptic terminals. This resulted in less calcium influx and, therefore, less transmitter release. Presynaptic inhibition and primary afferent depolarization could be blocked by antagonists of GABAA receptors, implying a role of interneurons that release gamma aminobutyric acid in the inhibitory circuit. The reason why afferent terminals were depolarized was later explained by a high intracellular concentration of Cl ions in primary sensory neurons. Activation of GABAA receptors opens Cl channels, and Cl efflux results in depolarization. Another proposed mechanism of depolarization was an increase in extracellular concentration of K+ following neural activity. Eccles’ work on presynaptic inhibition has since been extended in a variety of ways.

Introduction

Sir John Carew Eccles (1903–1997) was born near Melbourne, Australia (for biographical details, see: Katz, 1986, Curtis and Andersen, 2001, Mennis, 2003, Stuart and Pierce, 2006). Since both of his parents were teachers, he had a head start in his schoolwork. Eccles eventually attended Melbourne University where he chose to enroll in the medical curriculum. He graduated with Bachelor of Medicine and Bachelor of Surgery degrees in 1925. While a medical student, he read “The Integrative Action of the Nervous System” (1947) by Charles S. Sherrington (1857–1952). This gave him the ambition to go to the University of Oxford to work with Sherrington. He applied for and was awarded a Rhodes Scholarship (1925–1928). Rhodes Scholars are typically proficient in both academics and athletics. Eccles not only had good marks in his studies but he was also a record-setting pole vaulter. After spending half a year as a Resident Medical Officer in a hospital in Melbourne, he learned that he had been accepted by Oxford's Magdalen College where Sherrington was a Fellow (Fig. 1).

On arrival at Oxford in 1925, Eccles began a 2-year honors program in physiology and biochemistry, leading to a BA degree in 1927. This was followed by two years of research to earn his MA and PhD degrees in 1929. Eccles improved his English writing style through interactions with J.R.R. Tolkien (1892–1973) who was Professor of English and a Fellow of Magdalen College. In 1927, Eccles moved to Exeter College until 1934. He then returned to Magdalen College as a Tutorial Fellow and University Lecturer in Physiology. His work in Sherrington's laboratory at Oxford in 1925–1935 led to the publication of nearly 50 papers with Sherrington, G. Lindor Brown (1903–1971), Sybil Cooper (1900–1970), R. Stephen Creed (1898–1964), Derek Denny-Brown (1901–1981), Ragnar Granit (1900–1991), Hebbel E. Hoff (1907–1987), Edward G.T. Liddell (1895–1981), John Z. Young (1907–1997), and others (see Stuart and Pierce, 2006). The emphasis of the studies was on reflexes, especially the flexion reflex, and synaptic transmission, using the superior cervical sympathetic ganglion, smooth and cardiac muscle as model preparations. There was controversy at the time about whether synaptic transmission was electrical or chemical in nature. Eccles favored the view that it was, at least in part, electrical (see Burke, 2006). Eccles was invited by Sherrington to contribute to a book entitled “Reflex Activity of the Spinal Cord” as a co-author with Creed, Denny-Brown, Liddell and Sherrington (1932). In 1932, there was great excitement in the physiology department when Sherrington shared the Nobel Prize with Edgar D. Adrian (1889–1977) of Cambridge University.

Eccles remained at Oxford until 1937, when he returned to Australia to become Director of the Kanematsu Memorial Institute of Pathology in Sydney. In addition to supervising the clinical activities of the Institute, Eccles was able to develop research laboratories in which to study neuromuscular transmission. Initially, he collaborated with Walter J. O’Connor (1911–1984). He was soon joined by Stephen Kuffler (1913–1980), who had trained in Austria as a pathologist, and Bernard Katz (1911–2002), who had obtained a medical degree in Germany and then had joined the laboratory of Archibald V. (“AV”) Hill (1896–1977) in London where he was introduced to research in electrophysiology (Katz, 1986). This led to a PhD degree, which Katz obtained before coming to Sydney in 1939 (Fig. 2).

Kuffler and Katz were refugees from Europe because of the rise of Hitler. The Kanematsu group did pioneering work on the neuromuscular junction. In 1943, this extraordinary research team began to break up. Eccles accepted the Professorship of Physiology at the University of Otago in Dunedin, New Zealand. As World War II ended, Katz returned to London and Kuffler moved to the United States. Each had a distinguished career. Katz received the Nobel Prize in 1970, and Kuffler might also have been so recognized had he not died at an unexpectedly young age.

While Eccles was at the University of Otago, his research received a boost from his association with John (“Jack”) Coombs (1917–1993), a physicist who had learned radar electronics during the war (Fig. 3B). Coombs developed a modern electrophysiology laboratory for Eccles (Fig. 3A).

The new equipment like that shown in Fig. 3A allowed Eccles and his colleagues to perform the earliest intracellular recordings from spinal cord motoneurons (Brock et al., 1952; see also Brownstone, 2006, Burke, 2006). This enabled Eccles to test his idea that synaptic transmission in the spinal cord was electrical. Eccles and his colleagues had proposed that inhibition of spinal motoneurons by volleys in muscle afferents was mediated by electrotonic currents transmitted through short-axoned interneurons that passively depressed the excitability of motoneurons. Intracellular recordings showed that the inhibition was produced by an active hyperpolarization of the motoneuron membrane. The potential change was opposite to that predicted from Eccles’ hypothesis of electrical transmission and led to the rejection by Eccles of his hypothesis.

The Australian National University was founded in Canberra soon after World War II. Eccles became professor of physiology in the John Curtin School of Medical Research in 1951 and remained in that position until 1966. Coombs moved from New Zealand to Australia with Eccles to provide electronic support. The highly successful research program that Eccles developed in Canberra attracted scientists not only from Australia (such as David Curtis, Fig. 3C, and Eccles’ daughter Rosamund, Fig. 4D) and New Zealand (John Hubbard, 1930–1995, Fig. 3D-middle, and Victor McFarland, 1913–1982), but also from many other countries. According to Curtis and Andersen (2001), 41 investigators from 14 countries collaborated and published with Eccles during his Canberra period (see also Stuart and Pierce, 2006).

Just before he reached the mandatory retirement age of 65 years at the Australian National University, Eccles accepted a position in the Institute of Biomedical Research, which was being developed by the American Medical Association in its headquarters building in Chicago. He stayed in Chicago until 1968, when he again encountered a mandatory age limit. He then moved to the State University of New York at Buffalo, where he remained until his retirement to a village in Switzerland in 1975. After 1975, Eccles focused largely on the mind-brain problem (Curtis and Andersen, 2001, Wiesendanger, 2006, Libet, 2006). He died in 1997.

While I was a medical student at the University of Texas Southwestern Medical School in Dallas, Eccles visited that institution on a lecture tour. He gave two fascinating lectures. For the evening lecture, I was asked to project Eccles’ slides. This gave me an introduction to him and afterwards an opportunity to ask if he would ever consider taking on a trainee from the United States. He replied that he would consider doing this if the person had an appropriate background (for example, an MD, a DVM, or an MS degree in physiology with honors), obtained a letter of recommendation from a prominent neurophysiologist, and obtained an NIH Fellowship. I decided that I could meet these criteria by finishing my MD degree, and requesting a letter from Frank Harrison, who was dean of the local graduate school and a neurophysiologist who had trained with Stephen Ranson (1880–1942). I had worked in Harrison's laboratory during part of my medical school career. I also applied for and was awarded an NIH postdoctoral fellowship. My new wife and I arrived in Canberra in the summer of 1960 and we stayed until the summer of 1962, by which time I had completed my dissertation (Willis, 1962).

Before I continued postdoctoral studies with Giuseppe Moruzzi (1910–1986) in his Institute of Physiology in Pisa, Italy, I defended my dissertation in two oral one-on-one examinations while attending meetings in Europe. One exam was conducted by Ragnar Granit (1900–1991), from the Karolinska Institute, Stockholm, Sweden during a bus ride to a meeting in the Netherlands. The other exam was by Anders Lundberg, Department of Physiology, Göteborg University, Sweden on an airplane trip to Prague to attend another meeting.

Section snippets

Presynaptic inhibition

During his long and productive research career, Eccles did pioneering work in many fields of neurophysiology, one of which was presynaptic inhibition.

Prior to 1961, Eccles and his colleagues accomplished several important investigations of the ionic basis of excitation and inhibition of spinal cord motoneurons (e.g., Brock et al., 1952, Eccles et al., 1954, Coombs et al., 1955a, Coombs et al., 1955b, Coombs et al., 1955c; see review by Eccles, 1964). These studies were part of work on neuronal

GABA acting at GABAA receptors

Several mechanisms have been proposed to account for PAD. Pharmacological experiments showed that the administration of picrotoxin (but not strychnine) could block presynaptic inhibition of the monosynaptic reflex and the associated PAD in the cat spinal cord (Fig. 14; Eccles et al., 1963e). Picrotoxin blocks GABAA receptors, although not selectively.

Later experiments in the Canberra laboratory of David Curtis showed that GABA or GABAA receptor agonists released iontophoretically near group Ia

Differential control of PAD in different muscle afferent terminals

There is a higher concentration of presynaptic contacts on terminals of group Ia afferent fibers in the motor nucleus than in Clarke's column (Pierce and Mendell, 1993, Walmsley et al., 1995). The implication is that information conveyed by muscle afferents with branches to different targets can be controlled independently. This is consistent with findings in electrophysiological studies (Eguibar et al., 1997, Quevedo et al., 1997, Lomeli et al., 1998). For example, the PAD evoked in different

Role of DRRs in mechanical allodynia

Allodynia and hyperalgesia are commonly observed disturbances in many chronic pain patients. Allodynia is defined as pain due to a stimulus which does not normally provoke pain. Hyperalgesia is an increased response to a stimulus which is normally painful (Merskey and Bogduk, 1994). Cervero and Laird (1996) proposed a model for mechanical allodynia that involves presynaptic interactions similar to those suggested in the Gate Control Theory (Fig. 19).

Fig. 19 model is based on evidence that

Role of DRRs in neurogenic inflammation

One form of inflammation is termed “neurogenic inflammation” because it only occurs if the tissue is innervated (see Geppetti and Holzer, 1996). Changes that may occur during neurogenic inflammation include arteriolar vasodilation and plasma extravasation, leading to neurogenic edema (Szolcsányi, 1988). These changes result from the release of peptides and other substances from peripheral sensory nerve terminals (often referred to as an “efferent function” of primary afferent fibers; cf.,

Summary and concluding thoughts

Presynaptic inhibition in the monosynaptic reflex pathway from group Ia muscle spindle afferents to motoneurons was first reported by Frank and Fuortes in 1957. They named this type of inhibition “presynaptic” because they were able to demonstrate that conditioning volleys in another nerve could produce a depression of the monosynaptic excitatory postsynaptic potential (EPSP) in motoneurons without a change in (1) its time course, (2) the postsynaptic membrane potential, and (3) the

Acknowledgements

Research in the Willis laboratory has been supported by NIH grants NS09743 and NS11255. I thank Griselda Gonzales and Kelli Gondesen for their expert technical assistance.

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