Presynaptic calcium is increased during normal synaptic transmission and paired-pulse facilitation, but not in long-term potentiation in area CA1 of hippocampus

Abstract

We examined the relationship between presynaptic calcium levels and postsynaptic potentials during normal synaptic transmission, paired- pulse facilitation (PPF), and long-term potentiation (LTP) in CA3-CA1 synapses of hippocampus. By selectively loading the presynaptic terminals with the calcium indicator fura-2, we simultaneously recorded a presynaptic calcium (Ca) transient and the corresponding field EPSP evoked by a single stimulus given to the Schaffer collateral- commissural pathway in guinea pig hippocampal slices. A volume average presynaptic Ca influx was obtained by taking the first time derivative of the Ca transient. Our data indicate that the synaptic transmission represented by the initial slope of the field EPSP is approximately proportional to the fourth power of the presynaptic Ca influx, the volume average Ca current. Our results in combination with similar findings at the squid giant synapse (Augustine et al., 1985b; Augustine and Charlton, 1986) suggest that the relationship between Ca influx and transmitter release is well conserved from the molluscan to the mammalian nervous system. A transient increase of the residual Ca level ([Ca]res) is generally thought to be the mechanism underlying PPF (Katz and Miledi, 1968; Charlton et al., 1982); however, the relationship between PPF and the presynaptic [Ca]res had not been examined before. Our results demonstrate that PPF is approximately linearly related to the [Ca]res. This finding further supports the residual Ca hypothesis for PPF. Accumulated evidence from other groups suggests that the presynaptic site contributes to the maintenance of LTP in CA3-CA1 synapses (Bekkers and Stevens, 1990; Malinow and Tsien, 1990); however, our data show that neither an increase of the Ca transient nor a sustained increase of the [Ca]res occurs in the presynaptic terminals during maintenance of LTP. This suggests that the presynaptic mechanism underlying LTP must be downstream to Ca influx.

Postsynaptic Application of a Peptide Inhibitor of cAMP-Dependent Protein Kinase Blocks Expression of Long-Lasting Synaptic Potentiation in Hippocampal Neurons

“…This suggests that increased probability of transmitter release only briefly contributes to the induction of long-lasting LTP induced by repeated tetanization. This is consistent with published data supporting postsynaptic mechanisms for LTP induction in CA1 (Malinow et al, 1989;Wu and Saggau, 1994; for review, see Malenka and Nicoll, 1999). Our data do not rule out presynaptic contributions to the expression of tetanusinduced LTP at later time points after tetanization.…”

Long-term potentiation involves increases in the probability of neurotransmitter release

“…Evidence for this comes from examining quantal parameters (5,(31)(32)(33)(34)(35), presynaptic calcium transients during PPF (36), and the effect of altering membrane potential (37), and from finding that maneuvers that alter p are associated with changes in PPF (11,12,38). However, there is also evidence for a postsynaptic component to its expression (39).…”

“…The mechanism underlying LTP is evidently not an increase in presynaptic calcium influx (36), and therefore must be due to a downstream effect on p. There may be several other downstream factors that also affect p. LTP may appear to saturate, then, when a combination of factors causes p to reach a maximum. The contribution to p by LTP, however, may not be maximal at that point.…”

Postsynaptic Calcium Transients Evoked by Activation of Individual Hippocampal Mossy Fiber Synapses

“…Mossy fiber boutons display multiple discrete active zones (potential transmitter release sites) opposite postsynaptic densities on CA3 complex spines (Chicurel and Harris, 1992), so that the effective p r at these synapses is an aggregate probability reflecting both p r at each release site and the total number of these sites. Paired-pulse facilitation, the phenomenon in which the EPSP to a second closely-following stimulus is larger than that to the first, is believed to reflect an increase in p r to the second stimulus when residual Ca 2ϩ from the first impulse sums with Ca 2ϩ from the second (Wu and Saggau, 1994). In general, mossy fiber synapses exhibited a high p C a ; in 3 mM extracellular Ca 2ϩ , the average p C a was 0.84 Ϯ 0.05 (n ϭ 31 synapses).…”