Discrete synaptic states define a major mechanism of synapse plasticity Johanna M. Montgomery 1 and Daniel V. Madison 2 1 Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand 2 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA Synapses can change their strength in response to afferent activity, a property that might underlie a variety of neural processes such as learning, network synaptic weighting, synapse formation and pruning. Recent work has shown that synapses change their strength by jumping between discrete mechanistic states, rather than by simply moving up and down in a continuum of efficacy. Coincident with this, studies have provided a framework for understanding the potential mechanistic underpinnings of synaptic plastic states. Synaptic plasticity states not only represent a new and funda- mental property of CNS synapses, but also can provide a context for understanding outstanding issues in synap- tic function, plasticity and development. The fact that certain excitatory synapses in the brain can change their strength in response to activity has long captured the imaginations of neuroscientists. These changes might underlie such diverse processes as learning and memory, alterations in coding of information in neural networks, and synaptic development and elimination [1]. Synaptic plasticity of the type discussed here has primarily been studied in the excitatory glutamatergic synapses of the brain, particularly of the hippocampus. This review of synaptic properties and plasticity is confined to the widely studied subset of excitatory glutamatergic synapses that are efferent from hippocam- pal CA3 pyramidal cells to CA3 and CA1 postsynaptic neurons. These synapses have multiple subtypes of glutamate receptors in their postsynaptic membranes, including AMPA receptors, NMDA receptors) and meta- botropic glutamate (mGlu) receptors. Generally speaking, AMPA receptor subtypes mediate ion fluxes across the membrane during synaptic transmission at these synapses, whereas NMDA receptors and mGlu receptors are thought primarily to play a role in inducing or modulating plasticity of the AMPA-receptor-mediated transmission [2]. Persistent activity-dependent increases in synaptic transmission are referred to as long-term potentiation (LTP) [3] and decreases in synaptic transmission are termed long-term depression (LTD) [4,5]. Changes in synaptic strength can result from changes in glutamate receptor function [6], increased or decreased glutamate receptor expression in the postsynaptic density (PSD) [2], or changes in transmitter release, as at hippocampal mossy fiber terminals [7]. Blockade of postsynaptic exocytosis or endocytosis [by disrupting activity of N-ethylmaleimide-sensitive membrane fusion protein (NSF) [8] or inhibiting dynamin] prevents expression of LTP [9–11] and LTD, respectively [12–14]. Insertion of AMPA receptors into the synaptic membrane in an activity-dependent manner has been demonstrated using green fluorescent protein (GFP)-tagged AMPA receptor subunits [15,16]. Together with the finding that NMDA- receptor-mediated excitatory postsynaptic currents (EPSCs) do not change with increases in synaptic efficacy [17–19] (but see Refs [20,21]), these data show that potentiation or strengthening of excitatory synapses in the CA1 and CA3 regions of the hippocampus is associated with the specific recruitment and insertion of AMPA receptors from intracellular pools into the postsynaptic membrane [11,15]. Similarly, activity that causes synaptic depression, or a weakening of synaptic strength, is correlated with the endocytosis of these receptors from the postsynaptic membrane [12,22]. Thus, the response of a postsynaptic cell seems to be correlated with the number of AMPA receptors present on the postsynaptic mem- brane. In most cases, the insertion and removal of AMPA receptors is triggered by Ca 2C influx through NMDA receptors. This has led to the assertion that AMPA receptors are responsible for the expression of synaptic plasticity, whereas NMDA receptors are responsible for its control. Synaptic states: a mechanism of dictating synaptic strength A key role of synaptic plasticity is to allow the synapse to operate over a large dynamic range. Two possible models could explain the behavior of synapses over this range. In the first, synapses undergo changes in efficacy by adjust- ing their strength along a continuum, such that the properties of strengthening or weakening occur in a graded fashion with fixed underlying mechanisms (i.e. the ‘continuum model’). In the second, synapses might exist in different discrete states that represent and underlie different levels of efficacy (i.e. the ‘state model’). In an example of the continuum model utilizing AMPA receptor expression as an underlying mechanism, AMPA receptors are inserted or removed from the synaptic membrane and the cellular mechanisms regulat- ing their insertion or removal do not vary across the whole Corresponding author: Daniel V. Madison (madison@stanford.edu). Available online 14 October 2004 Review TRENDS in Neurosciences Vol.27 No.12 December 2004 www.sciencedirect.com 0166-2236/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2004.10.006