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Hypothesis regarding the cellular mechanisms responsible for long-term synaptic potentiation in the hippocampus
EXPERIMENTAL
NEUROLOGY
68, 202-204 (1980)
RESEARCH
NOTE
Hypothesis Regarding the Cellular Mechanisms Responsible for Long-Term Synaptic Potentiation in the Hippocampus MICHEL Department
of Psychobiology,
BAUDRY School Irvine, Received
AND GARY LYNCH
of Biological Sciences, Caljornia 92717 August
University
of California.
9, 1979
A possible cellular mechanism accounting for the long-term potentiation (LTP) of synaptic transmission in the hippocampus is presented. Our multiple-stage hypothesis postulates that repetitive stimulaion causes an increase of intracellular calcium in the target dendritic regions which results in the activation of a membrane-associated protease which in turn exposes additional glutamate receptors.
Hippocampal long-term potentiation (LTP) is a striking and unusual form of synaptic modulation. It is triggered by very brief events (high-frequency stimulation for a second or less) and when established persists for extraordinary periods (weeks). These properties suggest that the effect may have cellular substrates quite unlike those associated with more transient, decremental forms of synaptic facilitation and in the present note we should like to propose one possibility. Several lines of evidence point to the conclusion that LTP represents a lasting change in one or more components of the synaptic region (terminal, synapse, spine) and a recent experiment demonstrated that it is difficult to induce in the presence of below normal levels of extracellular calcium (4). This latter result may indicate that the effect is linked to transmitter release but it can also be taken as evidence that the trigger for LTP is an influx of calcium into the presynaptic and/or postsynaptic membranes. The second Abbreviation:
LTP-long-term
potentiation. 202
0014-4886/80/040202-03$02.00/O Copyright 0 1980 by Academic Press. Inc. All rights of reproduction m any form reserved
HIPPOCAMPAL
SYNAPTIC
POTENTIATION
AND
Ca
203
idea is an attractive one because of the wealth of data showing that even modest increases in intracellular calcium can produce dramatic effects including some which are quite persistent. If calcium were to produce LTP, how might this be accomplished? Although hardly conclusive, there is a substantial body of evidence pointing to the conclusion that glutamate or a closely related compound is the transmitter in several hippocampal pathways (7). Recently we found that hippocampal membranes possess two glutamate binding sites, one of which seems related to uptake while the other exhibits characteristics expected of a postsynaptic receptor (3). Experiments using isolated membranes indicate that calcium concentrations of 0.01 to 1.O mM markedly increase the number of binding sites of the second type and this effect persists even after the membranes are returned to solution with very low calcium concentrations (1). This raises the possibility that the number of glutamate receptors in hippocampal membranes is labile and can be increased by exposure to elevated calcium concentrations. There are a number of biochemical processes which might explain such an effect but a potential clue is provided by the observation that the effects of calcium are not found when membranes are incubated at low temperature. This implies that an enzymatic reaction may be involved and indeed we found that protease inhibitors reduce glutamate binding and block the effects of calcium upon such binding. Conversely, certain proteases, when added to hippocampal membranes, increase the number of glutamate binding sites (2). These findings can be integrated into the following multiple-stage hypothesis regarding the origins of long-term potentiation: (il repetitive stimulation causes an increase in intracellular calcium in the target dendritic regions, (ii) this results in the activation of a membrane-bound protease which (iii) exposes additional glutamate receptors (see Fig. I). The link between the protease and the glutamate
FIG. 1. Schematic hypothesis for long-term synaptic potentiation in the hippocampus. A postsynaptic dendritic region is schematically represented with glutamate receptors under two states, either exposed to the extracellular milieu or masked. The multiple-stage hypothesis postulates that repetitive electrical stimulation causes an influx ofcalcium 1) which increases the intracellular concentration of the cation 2) to a concentration high enough to 3) stimulate a membrane-associated protease which 4) directly or indirectly reveals new glutamate receptors.
204
BAUDRY
AND
LYNCH
binding sites is a subject for future experimentation but conceivably could be related to the neurofilament system [which is thought by some to be one constituent of the postsynaptic site (8)] and which appears to be linked to a calcium-activated protease (6) or to the presence of proteins which obscure the receptor [as was suggested to be the case for the GABA (y-aminobutyric acid) receptor (9)]. The postulated mechanism could serve to add receptors to existing synapses or be part of the formation of new or altered synaptic regions, an effect which appears to accompany LTP (5). In addition, it does not require new protein synthesis which is consistent with the fact that the induction of LTP is not impaired by protein synthesis inhibitors. This hypothesis would provide an explanation for the speed with which LTP appears as well as its duration. Studies to test whether the proposed mechanism is actually brought to play by repetitive stimulation of hippocampal synapses are currently in progress. REFERENCES 1. BAUDRY, M., AND G. LYNCH. 1979. Regulation of glutamate receptors by cations. Nature (London) 248, 748-750. 2. BAUDRY, M., AND G. LYNCH. 1979. Regulation of hippocampal glutamate receptors: evidence for the involvement of a calcium-activated protease. hoc. Natl. Acad. Sci. U.S.A. (in press). 3. BAUDRY, M., AND G. LYNCH. 1979. Two glutamate binding sites in rat hippocampal membranes. Ear. J. Pharm. 57: 283-285. 4. DUNWIDDIE. T. V., AND G. LYNCH. 1979. The relationship between extracellular calcium concentration and the induction of hippocampal long-term potentiation. Brain Res. 169: 103-110. 5. LEE, K., M. OLIVER, F. SCHOTTLER, R. CREAGER, ANDG. LYNCH. 1979. Ultrastructural effects of repetitive synaptic stimulation in the hippocampal slice preparation: A preliminary report. Exp. Neurol. 65: 478-480. 6. SCHLAEPFER, W. W., AND M. B. HASLER. 1979. Characterization of the calcium-induced disruption of neurofilaments in rat peripheral nerve. Brain Res. 168: 299-309. 7. STORM-MATHISEN, J. 1977. Localization of transmitter candidates in the brain: The hippocampal formation as a model. Prog. Neurobiol. 8: 119- 181. 8. TARRANT, S. B., AND A. ROUTTENBERG. 1979. Postsynaptic membranes and spine apparatus: proximity in dendritic spaces. Neurosci. Let?. 11: 289-294. 9. TOFFANO, G., A. GUIDOTTI, AND E. COSTA. 1978. Purification of an endogenous protein inhibitor of the high-affinity binding of y-aminobutyric acid to synaptic membranes of rat brain. Proc. Natl. Acad. Sci. 75, 6024-6028.
NEUROLOGY
68, 202-204 (1980)
RESEARCH
NOTE
Hypothesis Regarding the Cellular Mechanisms Responsible for Long-Term Synaptic Potentiation in the Hippocampus MICHEL Department
of Psychobiology,
BAUDRY School Irvine, Received
AND GARY LYNCH
of Biological Sciences, Caljornia 92717 August
University
of California.
9, 1979
A possible cellular mechanism accounting for the long-term potentiation (LTP) of synaptic transmission in the hippocampus is presented. Our multiple-stage hypothesis postulates that repetitive stimulaion causes an increase of intracellular calcium in the target dendritic regions which results in the activation of a membrane-associated protease which in turn exposes additional glutamate receptors.
Hippocampal long-term potentiation (LTP) is a striking and unusual form of synaptic modulation. It is triggered by very brief events (high-frequency stimulation for a second or less) and when established persists for extraordinary periods (weeks). These properties suggest that the effect may have cellular substrates quite unlike those associated with more transient, decremental forms of synaptic facilitation and in the present note we should like to propose one possibility. Several lines of evidence point to the conclusion that LTP represents a lasting change in one or more components of the synaptic region (terminal, synapse, spine) and a recent experiment demonstrated that it is difficult to induce in the presence of below normal levels of extracellular calcium (4). This latter result may indicate that the effect is linked to transmitter release but it can also be taken as evidence that the trigger for LTP is an influx of calcium into the presynaptic and/or postsynaptic membranes. The second Abbreviation:
LTP-long-term
potentiation. 202
0014-4886/80/040202-03$02.00/O Copyright 0 1980 by Academic Press. Inc. All rights of reproduction m any form reserved
HIPPOCAMPAL
SYNAPTIC
POTENTIATION
AND
Ca
203
idea is an attractive one because of the wealth of data showing that even modest increases in intracellular calcium can produce dramatic effects including some which are quite persistent. If calcium were to produce LTP, how might this be accomplished? Although hardly conclusive, there is a substantial body of evidence pointing to the conclusion that glutamate or a closely related compound is the transmitter in several hippocampal pathways (7). Recently we found that hippocampal membranes possess two glutamate binding sites, one of which seems related to uptake while the other exhibits characteristics expected of a postsynaptic receptor (3). Experiments using isolated membranes indicate that calcium concentrations of 0.01 to 1.O mM markedly increase the number of binding sites of the second type and this effect persists even after the membranes are returned to solution with very low calcium concentrations (1). This raises the possibility that the number of glutamate receptors in hippocampal membranes is labile and can be increased by exposure to elevated calcium concentrations. There are a number of biochemical processes which might explain such an effect but a potential clue is provided by the observation that the effects of calcium are not found when membranes are incubated at low temperature. This implies that an enzymatic reaction may be involved and indeed we found that protease inhibitors reduce glutamate binding and block the effects of calcium upon such binding. Conversely, certain proteases, when added to hippocampal membranes, increase the number of glutamate binding sites (2). These findings can be integrated into the following multiple-stage hypothesis regarding the origins of long-term potentiation: (il repetitive stimulation causes an increase in intracellular calcium in the target dendritic regions, (ii) this results in the activation of a membrane-bound protease which (iii) exposes additional glutamate receptors (see Fig. I). The link between the protease and the glutamate
FIG. 1. Schematic hypothesis for long-term synaptic potentiation in the hippocampus. A postsynaptic dendritic region is schematically represented with glutamate receptors under two states, either exposed to the extracellular milieu or masked. The multiple-stage hypothesis postulates that repetitive electrical stimulation causes an influx ofcalcium 1) which increases the intracellular concentration of the cation 2) to a concentration high enough to 3) stimulate a membrane-associated protease which 4) directly or indirectly reveals new glutamate receptors.
204
BAUDRY
AND
LYNCH
binding sites is a subject for future experimentation but conceivably could be related to the neurofilament system [which is thought by some to be one constituent of the postsynaptic site (8)] and which appears to be linked to a calcium-activated protease (6) or to the presence of proteins which obscure the receptor [as was suggested to be the case for the GABA (y-aminobutyric acid) receptor (9)]. The postulated mechanism could serve to add receptors to existing synapses or be part of the formation of new or altered synaptic regions, an effect which appears to accompany LTP (5). In addition, it does not require new protein synthesis which is consistent with the fact that the induction of LTP is not impaired by protein synthesis inhibitors. This hypothesis would provide an explanation for the speed with which LTP appears as well as its duration. Studies to test whether the proposed mechanism is actually brought to play by repetitive stimulation of hippocampal synapses are currently in progress. REFERENCES 1. BAUDRY, M., AND G. LYNCH. 1979. Regulation of glutamate receptors by cations. Nature (London) 248, 748-750. 2. BAUDRY, M., AND G. LYNCH. 1979. Regulation of hippocampal glutamate receptors: evidence for the involvement of a calcium-activated protease. hoc. Natl. Acad. Sci. U.S.A. (in press). 3. BAUDRY, M., AND G. LYNCH. 1979. Two glutamate binding sites in rat hippocampal membranes. Ear. J. Pharm. 57: 283-285. 4. DUNWIDDIE. T. V., AND G. LYNCH. 1979. The relationship between extracellular calcium concentration and the induction of hippocampal long-term potentiation. Brain Res. 169: 103-110. 5. LEE, K., M. OLIVER, F. SCHOTTLER, R. CREAGER, ANDG. LYNCH. 1979. Ultrastructural effects of repetitive synaptic stimulation in the hippocampal slice preparation: A preliminary report. Exp. Neurol. 65: 478-480. 6. SCHLAEPFER, W. W., AND M. B. HASLER. 1979. Characterization of the calcium-induced disruption of neurofilaments in rat peripheral nerve. Brain Res. 168: 299-309. 7. STORM-MATHISEN, J. 1977. Localization of transmitter candidates in the brain: The hippocampal formation as a model. Prog. Neurobiol. 8: 119- 181. 8. TARRANT, S. B., AND A. ROUTTENBERG. 1979. Postsynaptic membranes and spine apparatus: proximity in dendritic spaces. Neurosci. Let?. 11: 289-294. 9. TOFFANO, G., A. GUIDOTTI, AND E. COSTA. 1978. Purification of an endogenous protein inhibitor of the high-affinity binding of y-aminobutyric acid to synaptic membranes of rat brain. Proc. Natl. Acad. Sci. 75, 6024-6028.