Evidence that changes in presynaptic calcium currents are not responsible for long-term potentiation in hippocampus

We used two approaches to test the possibility that changes in presynaptic calcium currents might be responsible for the long-term potentiation (LTP) effect induced by high-frequency stimulation in area CA1 of hippocampal slices. In a first series of experiments, we compared the effect of LTP induction on paired-pulse facilitation with that produced by changes in extracellular calcium concentration, a procedure that modifies presynaptic calcium currents during depolarization by changing the ionic gradient for calcium. In hippocampus, as in peripheral synapses, increasing concentrations of extracellular calcium caused a marked reduction in the degree of facilitation obtained with paired-pulse stimulation; LTP, conversely, did not affect the facilitation ratio. The differential effect of changing calcium concentrations versus LTP induction on paired-pulse facilitation was observed with different interpulse intervals as well as in conditions in which the changes in response size produced by the two manipulations were comparable. In the second approach, we measured calcium dependency curves of synaptic responses before and after LTP induction or application of 4-aminopyridine, a blocker of potassium channels that increases presynaptic calcium currents by slowing spike repolarization. Procedures that increase calcium entry into terminals during transmission should shift to the left the sigmoidal function relating extracellular calcium to the slope of the extracellular response. This in turn should result in disproportionate effects of the procedure as a function of the calcium concentration. This prediction was realized with 4-aminopyridine but did not occur following LTP induction: control and potentiated responses were similarly affected by changes in calcium concentration. Although indirectly, these data strongly suggest that LTP is not accompanied by alterations in the presynaptic calcium dynamics associated with transmitter release.

[1]  R. Anwyl,et al.  The effects of external calcium on long-term potentiation in the rat hippocampal slice , 1988, Brain Research.

[2]  A. Wernig,et al.  Changes in statistical parameters during facilitation at the crayfish neuromuscular junction , 1972, The Journal of physiology.

[3]  G. Lynch,et al.  Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5 , 1986, Nature.

[4]  B. Katz,et al.  The role of calcium in neuromuscular facilitation , 1968, The Journal of physiology.

[5]  L. Nowak,et al.  Magnesium gates glutamate-activated channels in mouse central neurones , 1984, Nature.

[6]  G. Lynch,et al.  Stable hippocampal long-term potentiation elicited by ‘theta’ pattern stimulation , 1987, Brain Research.

[7]  Gary Lynch,et al.  The relationship between extracellular calcium concentrations and the induction of hippocampal long-term potentiation , 1979, Brain Research.

[8]  G Lynch,et al.  Brief bursts of high-frequency stimulation produce two types of structural change in rat hippocampus. , 1980, Journal of neurophysiology.

[9]  A Mallart,et al.  The relation between quantum content and facilitation at the neuromuscular junction of the frog , 1968, The Journal of physiology.

[10]  D. Muller,et al.  Inhibition of evoked acetylcholine release: two different mechanisms in the Torpedo electric organ. , 1987, European journal of pharmacology.

[11]  Edward W. Kairiss,et al.  Field potential evidence for long-term potentiation of feed-forward inhibition in the rat dentate gyrus , 1987, Brain Research.

[12]  W. Levy,et al.  Synaptic correlates of associative potentiation/depression: an ultrastructural study in the hippocampus , 1983, Brain Research.

[13]  B L McNaughton,et al.  Long‐term synaptic enhancement and short‐term potentiation in rat fascia dentata act through different mechanisms , 1982, The Journal of physiology.

[14]  G. Lynch,et al.  Induction of synaptic potentiation in hippocampus by patterned stimulation involves two events. , 1986, Science.

[15]  E. Kandel,et al.  Molecular biology of learning: modulation of transmitter release. , 1982, Science.

[16]  G. Lynch,et al.  Paired‐pulse and frequency facilitation in the CA1 region of the in vitro rat hippocampus , 1980, The Journal of physiology.

[17]  G. Lynch,et al.  Intracellular injections of EGTA block induction of hippocampal long-term potentiation , 1983, Nature.

[18]  S. Kelso,et al.  Hebbian synapses in hippocampus. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. Zucker.  Changes in the statistics of transmitter release during facilitation , 1973, The Journal of physiology.

[20]  G. Somjen,et al.  Calcium dependance of synaptic transmission in the hippocampal slice , 1981, Brain Research.

[21]  R. Zucker,et al.  Role of presynaptic calcium ions and channels in synaptic facilitation and depression at the squid giant synapse. , 1982, The Journal of physiology.

[22]  G. Lynch,et al.  Antagonism of NMDA receptors impairs acquisition but not retention of olfactory memory. , 1989, Behavioral neuroscience.

[23]  H. Wigström,et al.  Hippocampal long-term potentiation is induced by pairing single afferent volleys with intracellularly injected depolarizing current pulses. , 1986, Acta physiologica Scandinavica.

[24]  J. Miller,et al.  Calcium-induced long-term potentiation in the hippocampus , 1982, Neuroscience.

[25]  B. Katz,et al.  Estimates of quantal content during 'chemical potentiation' of transmitter release , 1979, Proceedings of the Royal Society of London. Series B. Biological Sciences.

[26]  T. Narahashi,et al.  Interactions of aminopyridines with potassium channels of squid axon membranes. , 1976, Biophysical journal.

[27]  W. Greenough.  Structural correlates of information storage in the mammalian brain: a review and hypothesis , 1984, Trends in Neurosciences.

[28]  P. Andersen,et al.  Calcium dependency of synaptic long-lasting potentiation in the hippocampal slice. , 1979, Acta physiologica Scandinavica.

[29]  H. Wigström,et al.  Facilitation of hippocampal long-lasting potentiation by GABA antagonists. , 1985, Acta physiologica Scandinavica.

[30]  S. J. Smith,et al.  Calcium action in synaptic transmitter release. , 1987, Annual review of neuroscience.

[31]  D. Muller.  Potentiation by 4‐aminopyridine of quantal acetylcholine release at the Torpedo nerve‐electroplaque junction. , 1986, The Journal of physiology.

[32]  G. Lynch,et al.  Rate‐limiting step for transmission at excitatory synapses in hippocampus , 1989, Synapse.

[33]  M. Mayer,et al.  The physiology of excitatory amino acids in the vertebrate central nervous system , 1987, Progress in Neurobiology.

[34]  P. Andersen,et al.  Specific long-lasting potentiation of synaptic transmission in hippocampal slices , 1977, Nature.

[35]  F. Dodge,et al.  Co‐operative action of calcium ions in transmitter release at the neuromuscular junction , 1967, The Journal of physiology.

[36]  G. Lynch,et al.  The biochemistry of memory: a new and specific hypothesis. , 1984, Science.

[37]  T. Bliss,et al.  NMDA receptors - their role in long-term potentiation , 1987, Trends in Neurosciences.

[38]  T. Bliss,et al.  Long-term potentiation of the perforant path in vivo is associated with increased glutamate release , 1982, Nature.