Abstract
The prevailing view at present is that postsynaptic expression of the classical NMDA receptor-dependent long-term potentiation relies on an increase in the numbers of local AMPA receptors (AMPARs). This is thought to parallel an expansion of postsynaptic cell specializations, for instance dendritic spine heads, which accommodate synaptic receptor proteins. However, glutamate released into the synaptic cleft can normally activate only a hotspot of low-affinity AMPARs that occur in the vicinity of the release site. How the enlargement of the AMPAR pool is causally related to the potentiated AMPAR current remains therefore poorly understood. To understand possible scenarios of postsynaptic potentiation, here we explore a detailed Monte Carlo model of the typical small excitatory synapse. Simulations suggest that approximately 50% increase in the synaptic AMPAR current could be provided by expanding the existing AMPAR pool at the expense of 100–200% new AMPARs added at the same packing density. Alternatively, reducing the inter-receptor distances by only 30–35% could achieve a similar level of current potentiation without any changes in the receptor numbers. The NMDA receptor current also appears sensitive to the NMDA receptor crowding. Our observations provide a quantitative framework for understanding the ‘resource-efficient’ ways to enact use-dependent changes in the architecture of central synapses.
Highlights
Cellular mechanisms of use-dependent synaptic plasticity remain a subject of intense investigation, because they hold a promise to unveil the neurobiological basis of learning and memory formation in the brain
The currently prevailing view is that the expression of classical NMDA receptor (NMDAR)dependent long-term potentiation (LTP) relies on the increased postsynaptic AMPA receptors (AMPARs) current, a boost in presynaptic release probability has been found important at least in some physiological scenarios [4,5,6]
Activation of higher affinity NMDARs is supposed to be much less sensitive to the distance from the glutamate release site compared with lower affinity AMPARs [18,35,36], our simulation results indicate that this distinction between AMPARs and NMDARs is less prominent inside the cleft
Summary
Cellular mechanisms of use-dependent synaptic plasticity remain a subject of intense investigation, because they hold a promise to unveil the neurobiological basis of learning and memory formation in the brain. The mechanism providing the LTPassociated AMPAR current increase is thought to involve activity-induced insertion of additional synaptic AMPARs through either endocytosis or lateral membrane trafficking, or both [7 –12] This paradigm could, in principle, explain a variety of physiological phenomena associated with a use-dependent functional and structural plasticity of excitatory synaptic connections [13]. Within the PSD, and how many additional AMPARs are normally required to explain robust synaptic potentiation remains poorly understood To address these questions in a quantitative manner, here we explore the relationship between the arrangement of AMPARs (and NMDARs) and synaptic efficacy at common excitatory synapses (exemplified by the CA3–CA1 connection in the hippocampus) using a computational Monte Carlo model. The duty cycle was repeated systematically throughout the model run
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