Bidirectional Synaptic Plasticity Correlated With the Magnitude of Dendritic Calcium Transients Above a Threshold

Abstract

The magnitude of postsynaptic Ca(2+) transients is thought to affect activity-dependent synaptic plasticity associated with learning and memory. Large Ca(2+) transients have been implicated in the induction of long-term potentiation (LTP), while smaller Ca(2+) transients have been associated with long-term depression (LTD). However, a direct relationship has not been demonstrated between Ca(2+) measurements and direction of synaptic plasticity in the same cells, using one induction protocol. Here, we used glutamate iontophoresis to induce Ca(2+) transients in hippocampal CA1 neurons injected with the Ca(2+)-indicator fura-2. Test stimulation of one or two synaptic pathways before and after iontophoresis showed that the direction of synaptic plasticity correlated with glutamate-induced Ca(2+) levels above a threshold, below which no plasticity occurred (approximately 180 nM). Relatively low Ca(2+) levels (180-500 nM) typically led to LTD of synaptic transmission and higher levels (>500 nM) often led to LTP. Failure to show plasticity correlated with Ca(2+) levels in two distinct ranges: <180 nM and approximately 450-600 nM, while only LTD occurred between these ranges. Our data support a class of models in which failure of Ca(2+) transients to affect transmission may arise either from insufficient Ca(2+) to affect Ca(2+)-sensitive proteins regulating synaptic strength through opposing activities or from higher Ca(2+) levels that reset activities of such proteins without affecting the net balance of activities. Our estimates of the threshold Ca(2+) level for LTD (approximately 180 nM) and for the transition from LTD to LTP (approximately 540 nM) may assist in constraining the molecular details of such models.

A large sustained Ca2+ elevation occurs in unstimulated spines during the LTP pairing protocol but does not change synaptic strength

“…Specifically, it was shown that a very high calcium elevation (calculated to be 12 M) that lasted for a few seconds often caused LTP and never caused LTD. In contrast, a long (1-min) elevation to a much smaller level (Ͻ1 M) reliably produced LTD. A shorter elevation (ϳ1 M for 10 s) could also induce LTD but surprisingly caused LTP in some cells Yang et al, 1999;Zucker, 1999; see also Cormier et al, 2001). These results point to the importance of concentration as a determinant of the sign of plasticity but suggest that temporal factors may also be relevant.…”

“…There is now substantial evidence that changes in intracellular Ca 2ϩ occur during the induction of LTP and LTD (Regehr and Tank, 1990;Muller and Connor, 1991;Otani and Connor, 1998;Cormier et al, 2001) and are responsible for triggering the synaptic modifications. In particular, it has been shown that both these processes can be blocked by intracellular injection of Ca 2ϩ buffers (Lynch et al, 1983;Malenka et al, 1988;Mulkey and Malenka, 1992).…”

A Specific Role for Ca2+-Dependent Adenylyl Cyclases in Recovery from Adaptive Presynaptic Silencing

“…In other words, strong Ca 2ϩ influx may activate silencing pathways that preclude the expression of the cAMP-dependent unsilencing mechanisms. This idea has precedent in the LTP literature, in which the level of Ca 2ϩ influx dictates the induction of either LTP or long-term depression (Abraham and Tate, 1997;Cormier et al, 2001). It is also possible that activity and cAMP signaling do not affect presynaptic function in a strictly linear pathway, although the ability of FSK to rescue presynaptic silencing induced by depolarization (Fig.…”

Stochastic Properties of Synaptic Transmission Affect the Shape of Spike Time–Dependent Plasticity Curves

“…The hypothesis that the sign and magnitude of synaptic plasticity is determined by calcium concentration in the postsynaptic spines (Lisman 1989) has received some direct and indirect experimental support (Cho et al 2001;Cormier et al 2001;Cummings et al 1996;Yang et al 1999).…”