Synapses in the brain are bidirectionally modifiable, but the routes of induction are diverse. In various experimental paradigms, N-methyl-D-aspartate receptor-dependent long-term depression and long-term potentiation have been induced selectively by varying the membrane potential of the postsynaptic neurons during presynaptic stimulation of a constant frequency, the rate of presynaptic stimulation, and the timing of pre-and postsynaptic action potentials. In this paper, we present a mathematical embodiment of bidirectional synaptic plasticity that is able to explain diverse induction protocols with a fixed set of parameters. The key assumptions and consequences of the model can be tested experimentally; further, the model provides the foundation for a unified theory of N-methyl-D-aspartate receptordependent synaptic plasticity.S ynapses throughout the brain are bidirectionally modifiable.This property, postulated in almost every theoretical description of synaptic plasticity, has been most clearly demonstrated at the Schaffer collateral-CA1 synapse in the hippocampus. Here, it was shown that a low-frequency tetanus induces long-term depression (LTD), whereas high-frequency stimulation produces long-term potentiation (LTP) of the stimulated synapses, and that LTD and LTP are inversely related (1-4). Similar results have been obtained at excitatory synapses throughout the brain.A considerable body of evidence indicates that the important variable is actually the amount of integrated postsynaptic N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation during conditioning (1, 2, 4-6). Modest NMDAR activation induces LTD, whereas strong activation produces LTP. Because of their voltage dependence, the contribution of NMDARs to synaptic transmission during conditioning stimulation varies with the level of postsynaptic depolarization. Thus, it is possible to induce LTD or LTP with a constant stimulation frequency by clamping the postsynaptic membrane potential at different values (approximately Ϫ50 mV for LTD and Ϫ20 mV for LTP).Recently, it has been demonstrated that synaptic modification also can depend on the precise timing of pre-and postsynaptic action potentials (7-11). If a presynaptic action potential occurs in a window of several tens of milliseconds before a back-propagating postsynaptic action potential, LTP is induced. In contrast, if a presynaptic action potential occurs after the postsynaptic spike, LTD is induced.Ideally, one would like to develop a unified description of bidirectional synaptic plasticity that can account for all routes of induction. One approach is to look beyond the various induction protocols to the critical role of calcium influx through NMDARs. One attractive idea is that modest increases in postsynaptic calcium trigger LTD, whereas large increases trigger . This hypothesis is consistent with the classical rate-based induction protocols if it is assumed that high-frequency stimulation triggers a larger rise in postsynaptic calcium than does low-frequency stimulation. Indeed, recent...

The receptive fields of visual cortical neurons are bidirectionally modified by sensory deprivation and experience, but the synaptic basis for these changes is unknown. Here we demonstrate bidirectional, experience-dependent regulation of the composition and function of synaptic NMDA receptors (NMDARs) in visual cortex layer 2/3 pyramidal cells of young rats. Visual experience decreases the proportion of NR2B-only receptors, shortens the duration of NMDAR-mediated synaptic currents, and reduces summation of synaptic NMDAR currents during bursts of high-frequency stimulation. Visual deprivation exerts an opposite effect. Although the effects of experience and deprivation are reversible, the rates of synaptic modification vary. Experience can induce a detectable change in synaptic transmission within hours, while deprivation-induced changes take days. We suggest that experience-dependent changes in NMDAR composition and function regulate the development of receptive field organization in visual cortex.

In reward-based learning, synaptic modifications depend on a brief stimulus and a temporally delayed reward, which poses the question of how synaptic activity patterns associate with a delayed reward. A theoretical solution to this so-called “distal reward problem” has been the notion of activity-generated ‘synaptic eligibility traces’, silent and transient synaptic tags that can be converted into long-term changes in synaptic strength by reward-linked neuromodulators. Here we report the first experimental demonstration of eligibility traces in cortical synapses. We demonstrate the Hebbian induction of distinct traces for LTP and LTD and their subsequent timing-dependent transformation into lasting changes by specific monoaminergic receptors anchored to postsynaptic proteins. Notably, the temporal properties of these transient traces allow stable learning in a recurrent neural network that accurately predicts the timing of the reward, further validating the induction/transformation of eligibility traces for LTP and LTD as a plausible synaptic substrate for reward-based learning.