Synapses display remarkable alterations in strength during repetitive use. Different types of synapses exhibit distinctive synaptic plasticity, but the factors giving rise to such diversity are not fully understood. To provide the experimental basis for a general model of short-term plasticity, we studied three synapses in rat brain slices at 34 degrees C: the climbing fiber to Purkinje cell synapse, the parallel fiber to Purkinje cell synapse, and the Schaffer collateral to CA1 pyramidal cell synapse. These synapses exhibited a broad range of responses to regular and Poisson stimulus trains. Depression dominated at the climbing fiber synapse, facilitation was prominent at the parallel fiber synapse, and both depression and facilitation were apparent in the Schaffer collateral synapse. These synapses were modeled by incorporating mechanisms of short-term plasticity that are known to be driven by residual presynaptic calcium (Ca(res)). In our model, release is the product of two factors: facilitation and refractory depression. Facilitation is caused by a calcium-dependent increase in the probability of release. Refractory depression is a consequence of release sites becoming transiently ineffective after release. These sites recover with a time course that is accelerated by elevations of Ca(res). Facilitation and refractory depression are coupled by their common dependence on Ca(res) and because increased transmitter release leads to greater synaptic depression. This model captures the behavior of three different synapses for various stimulus conditions. The interplay of facilitation and depression dictates synaptic strength and variability during repetitive activation. The resulting synaptic plasticity transforms the timing of presynaptic spikes into varying postsynaptic response amplitudes.

Short-term depression is a widespread form of use-dependent plasticity found in the peripheral and central nervous systems of invertebrates and vertebrates. The mechanism behind this transient decrease in synaptic strength is thought to be primarily the result of presynaptic "depletion" of a readily releasable neurotransmitter pool, which typically recovers with a time constant of a few seconds. We studied the mechanism and dynamics of recovery from depression at the climbing fiber to Purkinje cell synapse, where marked presynaptic depression has been described previously. Climbing fibers are well suited to studies of recovery from depression because they display little, if any, facilitation (even under conditions of low-release probability), which can obscure rapid recovery from depression for hundreds of milliseconds after release. We found that recovery from depression occurred in three kinetic phases. The fast and intermediate components could be approximated by exponentials with time constants of 100 msec and 3 sec at 24 degrees C. A much slower recovery phase was also present, but it was only prominent during prolonged stimulus trains. The fast component was enhanced by raising extracellular calcium and was eliminated by lowering presynaptic calcium, suggesting that, on short time scales, recovery from depression is driven by residual calcium. During regular and Poisson stimulus trains, recovery from depression was dramatically accelerated by accumulation of presynaptic residual calcium, maintaining synaptic efficacy under conditions that would otherwise deplete the available transmitter pool. This represents a novel form of presynaptic plasticity in that high levels of activity modulate the rate of recovery as well as the magnitude of depression.

A B S T R A C TVoltage-dependent gating behavior of Shaker potassium channels without N-type inactivation (ShBA6-46) expressed in Xenopus oocytes was studied.The voltage dependence of the steady-state open probability indicated that the activation process involves the movement of the equivalent of 12-16 electronic charges across the membrane. The sigmoidal kinetics of the activation process, which is maintained at depolarized voltages up to at least. + 100 mV indicate the presence of at least five sequential conformational changes before opening. The voltage dependence of the gating charge movement suggested that each elementary transition involves 3.5 electronic charges. The voltage dependence of the forward opening rate, as estimated by the single-channel first latency distribution, the final phase of the macroscopic ionic current activation, the ionic current reactivation and the ON gating current time course, showed movement of the equivalent of 0.3 to 0.5 electronic charges were associated with a large number of the activation transitions. The equivalent charge movement of 1.1 electronic charges was associated with the closing conformational change. The results were generally cofisistent with models involving a number of independent and identical transitions with a major exception that the first closing transition is slower than expected as indicated by tail current and OFF gating charge measurements.

Regulated delivery and removal of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors (GluRs) from postsynaptic elements has been proposed as a mechanism for regulating synaptic strength. Here we test the role of ubiquitin in regulating synapses that contain a C. elegans GluR, GLR-1. GLR-1 receptors were ubiquitinated in vivo. Mutations that decreased ubiquitination of GLR-1 increased the abundance of GLR-1 at synapses and altered locomotion behavior in a manner that is consistent with increased synaptic strength. By contrast, overexpression of ubiquitin decreased the abundance of GLR-1 at synapses and decreased the density of GLR-1-containing synapses, and these effects were prevented by mutations in the unc-11 gene, which encodes a clathrin adaptin protein (AP180). These results suggest that ubiquitination of GLR-1 receptors regulates synaptic strength and the formation or stability of GLR-1-containing synapses.