© 2004 by The Society for Integrative and Comparative Biology
Recent Developments in Neurobiology: Introduction to the Symposium1
1 Department of Biology, Arizona State University, Tempe, Arizona 85287-1501
2 Department of Biology, University of Kentucky, Lexington, Kentucky 40506-0225
This is the second of three annual "Recent Developments in Neurobiology" symposia supported by the Program Advisory Committee of the Society for Integrative and Comparative Biology (SICB). For the second consecutive year, we have received support from the National Science Foundation (IBN 0245736) to help support the speakers. We thank both SICB and NSF for their support.
One condition of SICB support was the implementation of an innovative program. Our wrinkle to the standard symposium structure has been successful beyond our highest expectation. Each symposium presentation is actually a "piggy-back" talk in which the head-of-lab gives the first half of the talk, providing a theoretical or practical overview of the lab's research program, followed by a presentation by a post-doc or advanced graduate student, highlighting current work from the lab. The "Recent Developments in Neurobiology" papers in this issue of Integrative and Comparative Biology are either joint papers by the two piggy-back authors, or separate papers by the two— the presenters were given the choice. We plan to continue this organizational scheme in the third year of the program, and beyond.
The "Recent Developments in Neurobiology" (RDN) format gives us maximum flexibility in topical organization of the symposia. We try to highlight labs from the vicinity of the annual meeting, and to give a broad spectrum of topics in the wide-ranging field of Neuroscience. For this reason the RDN symposia can be unusual. They do not have to be topic driven, and the contributed papers can be rather eclectic. The flexibility also gives us the opportunity to have a topical symposium when the opportunity arises. The first RDN symposium was of the former type, while the one presented here shows the latter. In this symposium, from Toronto, we chose to honor Professor Harold L. Atwood on the occasion of his retirement from the faculty of the University of Toronto (but, happily, not from neurobiological research).
The RDN symposium in honor of Professor Harold L. Atwood (Department of Physiology, University of Toronto), sponsored by the Division of Neurobiology within SICB is fitting for several reasons. One, of course, is his years of contribution in providing presentations to the American Society of Zoologists (now known as SICB) and having his students and postdoctoral fellows attend the annual meetings. In addition, Professor Atwood has contributed to the understanding of motor control for over forty years.
Harold received a BA from the University of Toronto in Biology, followed by an M.S. in Zoology at Berkeley. He received a Ph.D. as well as a D.Sc. in Neurophysiology from the University of Glasgow in Scotland. He has received many awards, fellowships and honors over the years, including a Guggenheim Fellowship at the Scripps Institute, La Jolla, California and election as a Fellow of the Royal Society of Canada. He has been associate editor, co-editor, and editor of several journals and series over the years, including the Canadian Journal of Physiology and Pharmacology, the Journal of Comparative Physiology, the Canadian Journal of Zoology, and the Biology of Crustacea, Vol. III. He has served in administrative roles for many societies and government funding agencies both in Canada and the USA. He was chair of the Department of Physiology of the Medical School at the University of Toronto for 10 years (1981–1991). Currently, he runs a very active research program at the University of Toronto in the Department of Physiology.
Harold's research program has addressed the physiology of muscular contraction, motor control, synaptic transmission, and synaptic modification in the nervous systems and neuromuscular systems of both arthropods (insects and crustaceans) and mammals. By far the largest part of his work has been on neuromuscular systems of crustaceans, which have been frequently studied by physiologists because their muscle cells and motor neurons attain a relatively large size and are relatively few in number (and thus readily identifiable in the intact animal or in isolated tissues). Beginning in the early 1960s, Harold and his students and co-workers discovered several new features of crustacean neuromuscular systems, which helped explain behavioral mechanisms. They also showed that the nerve cells of these animals undergo several activity-dependent long-term changes which have adaptive value for the animal, and appear to occur also in other animal species. The findings have general significance for the performance and experience-dependent modification of nervous and neuromuscular systems.
Investigating muscular contraction in crustaceans, Harold discovered in 1963 that crustacean muscles contain fast-acting and slow-acting muscle fibers (muscle cells) which are selectively recruited for fast and slow movements respectively. Subsequent studies with co-workers showed that the ultrastructure and biochemistry of the different muscle fibers are differentiated to accommodate the physiological demands they experience. In addition, studies on single innervated crab muscle cells showed that contraction is regulated by electrical events of the muscle cell membrane and not by direct chemical actions of the neurotransmitter. Significantly, the properties of synaptic transmission from motor neuron to muscle are matched with those of the muscle fibers: fast-acting muscle fibers are typically innervated by neurons which evoke large electrical responses in the muscle fiber, leading to large contractions, while slow-acting muscle fibers are typically supplied by neurons which evoke smaller electrical responses resulting in slow, graded contractions. Furthermore, specialized endings of a single motor neuron often produce different responses among the muscle fibers they innervate. Thus, a single neuron can selectively and progressively recruit the muscle fibers it innervates: at low frequencies of activity, only a few fibers contract, while at higher frequencies, as electrical activity increases, many more muscle fibers contract. In 1965 and 1967, Harold showed these features could be explained in large measure by the differences in release of excitatory neurotransmitter from individual nerve endings on their target muscle fibers; some nerve endings release more neurotransmitter, and thus cause a larger electrical response, than others. The same type of recruitment mechanism since has been observed by others, in the nervous systems of different animals ranging from leeches to mammals, and probably constitutes one of the many basic operational mechanisms of nervous systems.
Investigations combining ultrastructural and physiological observations of synapses led to several general principles of organization and operation. In 1967, he found that the inhibitory nerve cells that innervate crustacean muscles in parallel with the excitatory motor neurons, form well-defined synapses on the endings of the latter. These synapses account for the phenomenon of presynaptic inhibition (decrease in the release of excitatory neurotransmitter upon activation of the inhibitory nerve cell) which had first been described in crustacean muscles by Josef Dudel and Stephen Kuffler in 1961. Further work by Harold and his students led to a general model of this synaptic action, derived from the observed morphology and electrical properties of the nerve terminals, and to the observation that presynaptic inhibition apparently leads to fewer excitatory synapses effectively releasing neurotransmitter. Thus, an important principle of short-term response modification is variation in the number of a neuron's contributing synapses. In presynaptic inhibition, synapses are temporarily "decommissioned" to weaken the response; but in other cases, they are added to strengthen it.
Recruitment of additional synapses to strengthen a response, or strengthening of the responses of active synapses, was found to contribute to long- and short-term facilitation in crustaceans. Short-term facilitation is enhancement of synaptic transmission resulting from previous nerve impulses in a pathway, usually due to increased release of neurotransmitter, as originally described by Katz and Miledi in vertebrates, and by Dudel and Kuffler in crustaceans. Starting in the early 1970s, Dr. Atwood and co-workers produced three-dimensional reconstructions of nerve terminals from electron micrographs which allowed them to count all the individual synapses contributing to a local synaptic response. They found structural differences between "strong" and "weak" synapses, a finding which has been confirmed and amplified by C.K. Govind and others. In combination with statistical analyses of neurotransmission, begun by Atwood and Parnas in 1968, following the earlier work of Dudel and Kuffler, these studies led to the conclusion that individual synapses differ in effectiveness. Many synapses appear to be "silent" (do not release neurotransmitter) when a nerve cell is active at low frequencies.
A longer-lasting recruitment of synapses occurs during "long-term facilitation" (described by Sherman and Atwood for crustaceans in 1971); a very persistent enhancement of neurotransmission induced by a period of high-frequency activity. It has much in common with some forms of "long-term potentiation" now being intensively investigated in the mammalian nervous system as a possible mechanism contributing to learning and memory. Dr. Atwood and co-workers found the long-term effect in crustaceans was enhanced by accumulation of sodium and calcium ions in the presynaptic nerve terminal, increasing the release of neurotransmitter. They later showed long-lasting recruitment of additional synapses takes place in the presynaptic nerve endings to maintain the response at a higher level. They also found, as in the facilitatory responses analyzed by Eric Kandel and co-workers in molluscan nervous systems, the long-term effect in crustaceans depended upon the activation of the cyclic adenosine monophosphate (cyclic AMP) intracellular second-messenger system in the presynaptic nerve ending, triggering enhanced neurotransmission. However, they also found in 1975 and 1988 that, unlike several other analyzed cases, induction of this system depended primarily upon electrical activity in the nerve ending, and could occur without translocation of calcium ions into the nerve cell. Voltage-dependent activation of the cyclic AMP system has now been described by Daniel Storm and co-workers in other cell types, and may be of more general occurrence than is presently known.
An entirely different type of long-term modification in crustacean nerve cells was discovered in the early 1980s by Atwood and Lnenicka. When they altered the ongoing activity of a selected nerve cell in an intact animal, they found that a semi-permanent change in its synaptic transmission and morphology occurred. This modification was found (by Nguyen and Atwood) to depend upon protein synthesis in the affected nerve cell, and to involve several different intracellular mechanisms. The significance of the effect for nerve cells in general is that in many cases their properties are strongly influenced and continuously altered by ongoing activity ("experience"). This was found to be the case in a visual pathway of an insect nervous system by Bloom and Atwood in 1980.
Observations of this type in crustaceans and other animals raise the question of the relative importance of genetic limitations and "experience" in shaping the capabilities of the nervous system. The fruit fly, Drosophila, offers an opportunity to investigate this question; it has been extensively studied from the genetic standpoint, and its neuromuscular systems have much in common with those of crustaceans. Dr. Atwood began physiological and ultrastructural studies of synaptic transmission with Chun-Fang Wu, a leading authority on Drosophila neurophysiology, in 1991. He developed new physiological procedures (including a new physiological solution, since the one commonly in use for the previous two decades was found to rapidly damage the exposed cells). Once the basic physiology of selected synapses was worked out, work on the physiological consequences of genetic alteration of synapses was begun. Significantly, genetically induced structural perturbations can be physiologically compensated to maintain an appropriate level of synaptic transmission, indicating synaptic adaptation and an optimal "set point" for development of neurotransmission in a specific neural pathway. The nervous system can overcome certain genetic liabilities. Synaptic molecules discovered in Drosophila were shown to have close counterparts in crustaceans; thus, the way was opened for functional assays of gene products initially found in Drosophila, using crustacean neurons, which provide an experimentally more tractable system for physiological investigations.
Altogether, the work on crustacean and insect nerve cells has established several basic operational features, and provided insight into activity-dependent changes which are particularly well expressed in crustacean neurons, but are known to be of widespread occurrence in other animals. The combination of ultrastructural and physiological analysis of specific synapses developed by Harold and his co-workers has provided unique insights into factors determining the strength of responses in the nervous system, and how these responses can be modified.
We are proud to dedicate this symposium to Harold.
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FOOTNOTES |
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1 From the Symposium Recent Developments in Neurobiology presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 4–8 January 2003, at Toronto, Canada.
2 E-mail: rsatterlie{at}asu.edu
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Selected Bibliography Harold L. Atwood |
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Atwood, H. L. 1962. Depolarization and tension in crustacean muscle. Nature 195:387–388. The first observations on physiological differentiation of muscle fiber properties within a single muscle in the crustacean limb.
Atwood, H. L. 1963. Differences in muscle fibre properties as a factor in "fast" and "slow" contraction in Carcinus. Comp. Biochem. Physiol. 10:17–32. The first observations on physiological differentiation of muscle fiber properties in crustacean limb muscles, explaining features of the differences in contractions elicited by different motor axons.
Atwood, H. L., G. Hoyle, and T. Smyth. 1965. Mechanical and electrical responses of single innervated crab-muscle fibres. J. Physiol. (Lond.) 180:449–482. The relationship between synaptic transmission and muscle contraction was defined for crustacean muscles through studies of single innervated muscle fibers.
Atwood, H. L. 1967. Variation in physiological properties of crustacean motor synapses. Nature, Lond. 215:57–58. The first report on the presynaptic basis of "strong" and "weak" synapses of a single neuron.
Sherman, R. G., and H. L. Atwood. 1971. Synaptic facilitation: Long-term neuromuscular facilitation in crustacean muscles. Science 171:1248–1250. The first report on long-term facilitation (a form of long-term potentiation).
Jahromi, S. S., and H. L. Atwood. 1974. Three-dimensional ultrastructure of the crayfish neuromuscular apparatus. J. Cell Biol. 63:599–613. The first 3-dimensional characterization of crustacean neuromuscular junctions, "active zones," and possible "silent" synapses.
Atwood, H. L., L. E. Swenarchuk, and C. R. Gruenwald. 1975. Long-term synaptic facilitation during sodium accumulation in nerve terminals. Brain Research 100:198–204. Ionic events linked to long-term facilitation were analyzed.
Atwood, H. L., C. K. Govind, and I. Kwan. 1977. Non-homogeneous excitatory synapses of a crab stomach muscle. J. Neurobiology, 9:17–28. Ultrastructural basis for "strong" and "weak" synapses examined; synaptic complexity varies among individual synapses of a single terminal.
Lnenicka, G. A., and H. L. Atwood. 1985. Age-dependent long-term adaptation of crayfish phasic motor axon synapses to altered activity. J. Neuroscience 5:459–467. First description of long-term adaptation of synaptic transmission due to altered neural activity.
Wojtowicz, J. M., and H. L. Atwood. 1986. Long-term facilitation alters transmitter releasing properties at the crayfish neuromuscular junction. J. Neurophysiol. 55:484–498. First quantal analysis of long-term facilitation; evidence for new synapses being recruited to enhance synaptic transmission.
Lnenicka, G. A., H. L. Atwood, and L. Marin. 1986. Morphological transformation of synaptic terminals of a phasic motoneuron by long-term tonic stimulation. J. Neurosci. 6:2252–2258. First description of morphological transformation of synaptic terminals by altered activity. Synapses adapt to meet the demands of activity.
Wojtowicz, J. M., and H. L. Attwood. 1988. Presynaptic long-term facilitation at the crayfish neuromuscular junction: Voltage-dependent and ion-dependent phases. J. Neurosci. 8:4667–4674. Detailed analysis of ionic events necessary for long-term facilitation; calcium entry is not required for maintained enhancement of transmission.
Dixon, D., and H. L. Atwood. 1989. Adenylate cyclase system is essential for long-term facilitation at the crayfish neuromuscular junction. J. Neurosci. 9:4246–4252. Requirement of cAMP for long-term facilitation in crayfish terminals.
Cooper, R. L., L. Marin, and H. L. Atwood. 1995. Synaptic differentiation of a single motor neuron: Conjoint definition of transmitter release, presynaptic calcium signals, and ultrastructure. J. Neurosci. 15:4209–4222. The first studies in direct structural relationship from regions of the nerve terminals in which physiological measures were obtained.
Karunanithi, S., L. Marin, K. Wong, and H. L. Attwood. 2002. Quantal size and variation determined by vesicle size in normal and mutant Drosophila glutamatergic synapses. J. Neurosci. 22: 10267–10276.
Millar, A. G., H. Bradacs, M. P. Charlton, and H. L. Atwood. 2002. Inverse relationship between release probability and readily releasable vesicles in depressing and facilitating synapses. J. Neurosci. 22:9661–9667.
Song, W., R. Ranjan, K. Dawson-Scully, P. Bronk, L. Marin, L. Seroude, Y.J. Lin, Z. Nie, H. L. Atwood, S. Benzer, and K.E. Zinsmaier. 2002. Presynaptic regulation of neurotransmission in Drosophila by the g protein-coupled receptor Methuselah. Neuron 36:105–119.
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