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Graham Goddard (1938–1987)
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t r i b u t e
GrahamGoddard(193 - 1987) Ronald J. Racine RonaldJ. Racineisat the Departmentof Psychology, McMasterUniversily, Hamilton,Ontario L854K1, Canada.
Graham Goddard was killed tragically #7 a hiking accident at the beginning of this year. Twenty years ago he discovered the phenomenon of kindling, which has been an important stimulusinduced model for epilepsy. More recently he had come to be interested in synaptic plasticity and LTP. Here, his colleague, Ronald Racine, gives a brief overview of Goddard and his contributions.
Graham Valentine Goddard, 48 years old, died on January 15, 1987 while hiking along the Mingha Deception River trail in the Arthur's Pass area of New Zealand's South Island. He was on the trip with his wife, Patricia, and his two-year-old son, Eric. One of Pat's hiking boots had fallen apart during the hike, and she could no longer continue. They set up camp and the next day tried to signal for help. Eventually, Graham decided that he should hike out to obtain help. A continual rain had caused the Deception River, difficult at the best of times, to rise. Graham was apparently swept away while trying to cross the river and was subsequently drowned. Pat and Eric were spotted by a helicopter pilot and picked up the next day. A search for Graham was then mobilized from nearby Otira. His body was found at the junction of the Deception and Otira rivers. Graham Goddard was born in England in 1938 and emigrated to Canada in 1954. He completed his undergraduate work at the University of Saskatchewan, and obtained his Master's degree from the same University in 1961. He completed his PhD studies at McGill University in Montreal. His doctoral research was on the role of the amygdala in learning and memory I. While at McGill, Graham was heavily influenced by Donald Hebb, and he continued to think about 'big picture' issues in neurosciences while working at a relatively molecular level of analysis in the laboratory.
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Graham Goddard
354
!iiii ¸¸
After McGill, Graham took up an assistant professorship at the University of Waterloo, in Waterloo, Ontario, Canada. It was there that he first realized the importance of his observation that repeated electrical stimulation of the arnygdala often led to the eventual triggering of convulsive activity. Brief, low intensity stimulation trains that initially produced no observable effect on behaviour would eventually come to trigger a fully generalized convulsive response2. While this effect had been observed before, it had generally been considered to be a major annoyance in any experiment utilizing brain stimulation. Graham was particularly intrigued by the permanence of the effect, which he subsequently called 'kindling'. He recognized the value of kindling as an epilepsy model. It provided a chronic preparation with fewer confounding variables than the chemical lesion models. He also believed that the changes in neural function leading to increased epileptogenesis might involve some of the same mechanisms used in engram formation. I met Graham in the spring of 1966, when he came to Montreal to use the Medical Library at McGill to find out more about this new phenomenon. I was impressed by the clarity with which he described its possibilities as a memory model. He returned to Waterloo to pursue his investigations with the help of his first graduate students, Dan Mclntyre and Curtis Leech3. In 1969, Graham moved to Dalhousie University, in Halifax, Nova Scotia, as an Associate Professor. He became a Full Professor at the same university in 1973. While at Dalhousie, he became interested in the new phenomenon of 'long-term potentiation' (LTP). He and his students, Bruce McNaughton, Rob Douglas and Carole Barnes, completed several experiments that stand as some of the best work that has been done in that area. The projects completed during this period include an analysis of interactions between co-active pathways in the induction of hippocampal LTP4. Graham continued to see these examples of 'cooperativity' as useful models of associative memory mechanisms. Related to these observations was the work done on the modulatory effects of inhibitory pathways on hippocampal LTP5. It was found that co-active inhibitory inputs could block LTP. However, this effect did not appear to be related to the suppression of cell discharge. Another excitFng area of research during this period involved a direct comparison of spatial memory, believed to require hippocampal processing, and LTP effects in the hippocampus. The comparisons were made in both old and young rats and a significant correlation was found between the rate of decay of the memory and the rate of decay of LTP6. Although remaining active in research, Graham also became interested in administration. Just as in his research work, however, he was interested in
© 1987.ElsevierPublications.Cambridge0378-5912/87/$02.00
TINS, Vol. 10, No. 9, 1987
ture. As a young man he raced motorcycles, and he and his wife once travelled from Canada to Peru by motorcycle. In New Zealand, he continued to pursue his interests in motorcycles, as well as skiing, hiking, mountain climbing and sailing. He was willing to try almost anything. Graham leaves behind many students, friends and colleagues who will miss his ability to bring the research effort to life by witty and insightful observation.
creating something of value. It is not surprising, then, that he began to look for a chairmanship position. The position that Graham finally accepted was at the University of Otago in Dunedin, New Zealand, which turned out to be an excellent choice. The Psychology Department there was about to enter a period of growth. Graham took this opportunity to build a truly excellent department and one of the leading neuroscience programs in the Southern Hemisphere. Graduate students, such as Dave Bilkey 7 and Mike Dra~unow 8, postdoctoral fellows, such as Cliff Abraham ~ and Ed Kairiss 1°, and visiting scientists, such as Kiyoshi Morimoto 11, ensured the continued high quality of his own laboratory work. Graham clearly enjoyed administrative work, and had recently agreed to serve for another term as chairman. He still had enough energy to embark on an additional research program concerning the use of computer-assisted tests (including games and simulations) to assess various neuropsychological disorders 12. His first area of interest, however, continued to be memory, and he was planning to spend a year's research leave in the laboratory of Tim Bliss working on the long-term potentiation model of memory. He was particularly interested in the recent evidence implicating the NMDA receptor in the LTP phenomenon 13. Graham served on many boards and committees. His non-academic interests, however, provide more insight into the nature of the man. As busy as he was professionally, he always made time for adven-
Selectedreferences 1 2 3 4
Goddard,G. V. (1964) J. Comp. Physiol. Psychol. 58, 23-30 Goddard, G. V. (1967) Nature 214, 1020-1021 Goddard, G. V. (1969) Exp. Neurol. 25, 295-330 McNaughton, B. L., Douglas, R.M. and Goddard, G.V. (1978) Brain Res. 157, 277-293 5 Douglas, R. M., Goddard, G. V. and Rives, M. (1982) Brain Res. 240, 259-272 6 Barnes,C. A. (1979) J. Comp. Physiol. Psychol. 93, 74-104 7 Bilkey, D. K. and Goddard, G. V. (1985) Brain Res. 361,99106 8 Dragunow, M. and Goddard, G. V. (1983) Exp. Neurol. 84, 654-665 9 Abraham, W. C., Bliss,T. V. P. and Goddard, G, V. (1985) J. Physiol. (London) 363, 335-349 10 Kairiss, E. W., Abraham, W. C., Bilkey, D. K. and Goddard, G. V. (1986) Brain Res. 401, 87-94 11 Morimoto, K. and Goddard, G.V. (1986) Exp. Neurol. 94, 571-584 12 Davidson,O. R., Stevens,D. E., Goddard, G. V., Bilkey, D. K. and Bishara, S.N. Applied Psychology: An International Review (in press) 13 Wigstrom, H. and Gustaffson, B. (1984) Neurosci. Lett. 44, 327-332
strange features: for example, the Receptor-G protein ligand is released after every actiprecoupling: neither proven vation of one G protein by a nor needed receptor. This does not accomSI~: The scheme of receptor activation presented by A.C. Dolphin on the front page of TINS (February 1987) 1, and the accompanying figure propagate what I think is a misconception of the role of G proteins in signal transduction. As diagrammed and stated, the G protein would interact with the receptor, before any binding of the signal molecule, to induce its transformation to a state of high affinity (R*) for the ligand: G-GDP+ R-,R*-G-GDP. Then, without any further conformational change of the receptor, ligand binding allows GDP/GTP exchange on G. Thereafter, G ~-GTP and GI3~ are released from R*, which would then switch back to its Iow-ligand affinity state R. The ligand would then be released. In this scheme, the G protein, not the signal molecule, plays the major role in activating the receptor. This view results in several TIN& Vol. 10, No. 9, 1987
modate the amplification of the response by a pool of G proteins and is hard to reconcile with recent data on ligand-dependent receptor phosphorylation and regulation 2. The only support for this scheme comes, I believe, from a suspicious interpretation of the well-known GTP dependence of ligand affinity of receptors 3. Contrary to Dolphin's assumption, this does not require a modification of the ligand site by precoupling of G with unliganded R. Affinity assays measure only the ratio of two kinetic constants (Kb/Kd) that define the equilibrium:
Kb R+L
~
R*L
Ke The binding constant Kb depends on the site conformation in unliganded R, and the dissociation constant Kd on its conformation in the R*L state. Affinity data obtained from binding assays
(necessarily in the presence of ligand), do not only assess the state of R before ligand binding. An affinity increase may result from a decrease of Kd due to an interaction of G with R'L, rather than from an increase of Kb due to an interaction of G with unliganded R. The former is clearly the case for the visual receptor rhodopsin and its G protein transducin (T), a system now recognized as a good model for G protein-mediated transduction 2'4. Here the ligand, retinal, is already bound to the receptor, but in an inactive conformation I, until it is photoisomerized. In the dark, R does not interact with T, which is easily extractable. Light gives the ligand its active conformation L, which triggers a conformational transition RI--,R*L. This is independent of the presence of T. Only then does T-GDP bind to R'L, forming a R*L-T complex, which remains permanent if GTP has been suppressed from the medium 5. If the number of photoexcited rhodopsins is less than that of transducins, all R*L are complexed as
We welcome commentsfromour readers.Short communicabons standthe bestchance of publication, and the editorreservesthe right to takeextracts from the Ion&erones.
355
.
.
.
.
t r i b u t e
GrahamGoddard(193 - 1987) Ronald J. Racine RonaldJ. Racineisat the Departmentof Psychology, McMasterUniversily, Hamilton,Ontario L854K1, Canada.
Graham Goddard was killed tragically #7 a hiking accident at the beginning of this year. Twenty years ago he discovered the phenomenon of kindling, which has been an important stimulusinduced model for epilepsy. More recently he had come to be interested in synaptic plasticity and LTP. Here, his colleague, Ronald Racine, gives a brief overview of Goddard and his contributions.
Graham Valentine Goddard, 48 years old, died on January 15, 1987 while hiking along the Mingha Deception River trail in the Arthur's Pass area of New Zealand's South Island. He was on the trip with his wife, Patricia, and his two-year-old son, Eric. One of Pat's hiking boots had fallen apart during the hike, and she could no longer continue. They set up camp and the next day tried to signal for help. Eventually, Graham decided that he should hike out to obtain help. A continual rain had caused the Deception River, difficult at the best of times, to rise. Graham was apparently swept away while trying to cross the river and was subsequently drowned. Pat and Eric were spotted by a helicopter pilot and picked up the next day. A search for Graham was then mobilized from nearby Otira. His body was found at the junction of the Deception and Otira rivers. Graham Goddard was born in England in 1938 and emigrated to Canada in 1954. He completed his undergraduate work at the University of Saskatchewan, and obtained his Master's degree from the same University in 1961. He completed his PhD studies at McGill University in Montreal. His doctoral research was on the role of the amygdala in learning and memory I. While at McGill, Graham was heavily influenced by Donald Hebb, and he continued to think about 'big picture' issues in neurosciences while working at a relatively molecular level of analysis in the laboratory.
!
Graham Goddard
354
!iiii ¸¸
After McGill, Graham took up an assistant professorship at the University of Waterloo, in Waterloo, Ontario, Canada. It was there that he first realized the importance of his observation that repeated electrical stimulation of the arnygdala often led to the eventual triggering of convulsive activity. Brief, low intensity stimulation trains that initially produced no observable effect on behaviour would eventually come to trigger a fully generalized convulsive response2. While this effect had been observed before, it had generally been considered to be a major annoyance in any experiment utilizing brain stimulation. Graham was particularly intrigued by the permanence of the effect, which he subsequently called 'kindling'. He recognized the value of kindling as an epilepsy model. It provided a chronic preparation with fewer confounding variables than the chemical lesion models. He also believed that the changes in neural function leading to increased epileptogenesis might involve some of the same mechanisms used in engram formation. I met Graham in the spring of 1966, when he came to Montreal to use the Medical Library at McGill to find out more about this new phenomenon. I was impressed by the clarity with which he described its possibilities as a memory model. He returned to Waterloo to pursue his investigations with the help of his first graduate students, Dan Mclntyre and Curtis Leech3. In 1969, Graham moved to Dalhousie University, in Halifax, Nova Scotia, as an Associate Professor. He became a Full Professor at the same university in 1973. While at Dalhousie, he became interested in the new phenomenon of 'long-term potentiation' (LTP). He and his students, Bruce McNaughton, Rob Douglas and Carole Barnes, completed several experiments that stand as some of the best work that has been done in that area. The projects completed during this period include an analysis of interactions between co-active pathways in the induction of hippocampal LTP4. Graham continued to see these examples of 'cooperativity' as useful models of associative memory mechanisms. Related to these observations was the work done on the modulatory effects of inhibitory pathways on hippocampal LTP5. It was found that co-active inhibitory inputs could block LTP. However, this effect did not appear to be related to the suppression of cell discharge. Another excitFng area of research during this period involved a direct comparison of spatial memory, believed to require hippocampal processing, and LTP effects in the hippocampus. The comparisons were made in both old and young rats and a significant correlation was found between the rate of decay of the memory and the rate of decay of LTP6. Although remaining active in research, Graham also became interested in administration. Just as in his research work, however, he was interested in
© 1987.ElsevierPublications.Cambridge0378-5912/87/$02.00
TINS, Vol. 10, No. 9, 1987
ture. As a young man he raced motorcycles, and he and his wife once travelled from Canada to Peru by motorcycle. In New Zealand, he continued to pursue his interests in motorcycles, as well as skiing, hiking, mountain climbing and sailing. He was willing to try almost anything. Graham leaves behind many students, friends and colleagues who will miss his ability to bring the research effort to life by witty and insightful observation.
creating something of value. It is not surprising, then, that he began to look for a chairmanship position. The position that Graham finally accepted was at the University of Otago in Dunedin, New Zealand, which turned out to be an excellent choice. The Psychology Department there was about to enter a period of growth. Graham took this opportunity to build a truly excellent department and one of the leading neuroscience programs in the Southern Hemisphere. Graduate students, such as Dave Bilkey 7 and Mike Dra~unow 8, postdoctoral fellows, such as Cliff Abraham ~ and Ed Kairiss 1°, and visiting scientists, such as Kiyoshi Morimoto 11, ensured the continued high quality of his own laboratory work. Graham clearly enjoyed administrative work, and had recently agreed to serve for another term as chairman. He still had enough energy to embark on an additional research program concerning the use of computer-assisted tests (including games and simulations) to assess various neuropsychological disorders 12. His first area of interest, however, continued to be memory, and he was planning to spend a year's research leave in the laboratory of Tim Bliss working on the long-term potentiation model of memory. He was particularly interested in the recent evidence implicating the NMDA receptor in the LTP phenomenon 13. Graham served on many boards and committees. His non-academic interests, however, provide more insight into the nature of the man. As busy as he was professionally, he always made time for adven-
Selectedreferences 1 2 3 4
Goddard,G. V. (1964) J. Comp. Physiol. Psychol. 58, 23-30 Goddard, G. V. (1967) Nature 214, 1020-1021 Goddard, G. V. (1969) Exp. Neurol. 25, 295-330 McNaughton, B. L., Douglas, R.M. and Goddard, G.V. (1978) Brain Res. 157, 277-293 5 Douglas, R. M., Goddard, G. V. and Rives, M. (1982) Brain Res. 240, 259-272 6 Barnes,C. A. (1979) J. Comp. Physiol. Psychol. 93, 74-104 7 Bilkey, D. K. and Goddard, G. V. (1985) Brain Res. 361,99106 8 Dragunow, M. and Goddard, G. V. (1983) Exp. Neurol. 84, 654-665 9 Abraham, W. C., Bliss,T. V. P. and Goddard, G, V. (1985) J. Physiol. (London) 363, 335-349 10 Kairiss, E. W., Abraham, W. C., Bilkey, D. K. and Goddard, G. V. (1986) Brain Res. 401, 87-94 11 Morimoto, K. and Goddard, G.V. (1986) Exp. Neurol. 94, 571-584 12 Davidson,O. R., Stevens,D. E., Goddard, G. V., Bilkey, D. K. and Bishara, S.N. Applied Psychology: An International Review (in press) 13 Wigstrom, H. and Gustaffson, B. (1984) Neurosci. Lett. 44, 327-332
strange features: for example, the Receptor-G protein ligand is released after every actiprecoupling: neither proven vation of one G protein by a nor needed receptor. This does not accomSI~: The scheme of receptor activation presented by A.C. Dolphin on the front page of TINS (February 1987) 1, and the accompanying figure propagate what I think is a misconception of the role of G proteins in signal transduction. As diagrammed and stated, the G protein would interact with the receptor, before any binding of the signal molecule, to induce its transformation to a state of high affinity (R*) for the ligand: G-GDP+ R-,R*-G-GDP. Then, without any further conformational change of the receptor, ligand binding allows GDP/GTP exchange on G. Thereafter, G ~-GTP and GI3~ are released from R*, which would then switch back to its Iow-ligand affinity state R. The ligand would then be released. In this scheme, the G protein, not the signal molecule, plays the major role in activating the receptor. This view results in several TIN& Vol. 10, No. 9, 1987
modate the amplification of the response by a pool of G proteins and is hard to reconcile with recent data on ligand-dependent receptor phosphorylation and regulation 2. The only support for this scheme comes, I believe, from a suspicious interpretation of the well-known GTP dependence of ligand affinity of receptors 3. Contrary to Dolphin's assumption, this does not require a modification of the ligand site by precoupling of G with unliganded R. Affinity assays measure only the ratio of two kinetic constants (Kb/Kd) that define the equilibrium:
Kb R+L
~
R*L
Ke The binding constant Kb depends on the site conformation in unliganded R, and the dissociation constant Kd on its conformation in the R*L state. Affinity data obtained from binding assays
(necessarily in the presence of ligand), do not only assess the state of R before ligand binding. An affinity increase may result from a decrease of Kd due to an interaction of G with R'L, rather than from an increase of Kb due to an interaction of G with unliganded R. The former is clearly the case for the visual receptor rhodopsin and its G protein transducin (T), a system now recognized as a good model for G protein-mediated transduction 2'4. Here the ligand, retinal, is already bound to the receptor, but in an inactive conformation I, until it is photoisomerized. In the dark, R does not interact with T, which is easily extractable. Light gives the ligand its active conformation L, which triggers a conformational transition RI--,R*L. This is independent of the presence of T. Only then does T-GDP bind to R'L, forming a R*L-T complex, which remains permanent if GTP has been suppressed from the medium 5. If the number of photoexcited rhodopsins is less than that of transducins, all R*L are complexed as
We welcome commentsfromour readers.Short communicabons standthe bestchance of publication, and the editorreservesthe right to takeextracts from the Ion&erones.
355