A biophysical model of bidirectional synaptic plasticity: Dependence on AMPA and NMDA receptors

doi:10.1073/pnas.201404598

A biophysical model of bidirectional synaptic plasticity: Dependence on AMPA and NMDA receptors

^*Physics Department, CIG and Dimorfipa Bologna University, Bologna 40121, Italy; ^†Department of Biology, University of Maryland, College Park, MD 20742; and ^‡Institute for Brain and Neural Systems, ^§Department of Neuroscience, and ^¶Department of Physics, Brown University, Providence, RI 02912

Contributed by Leon N Cooper

Abstract

In many regions of the brain, including the mammalian cortex, the magnitude and direction of activity-dependent changes in synaptic strength depend on the frequency of presynaptic stimulation (synaptic plasticity), as well as the history of activity at those synapses (metaplasticity). We present a model of a molecular mechanism of bidirectional synaptic plasticity based on the observation that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD) correlate with the phosphorylation/dephosphorylation of sites on the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit protein GluR1. The primary assumption of the model, for which there is wide experimental support, is that postsynaptic calcium concentration and consequent activation of calcium-dependent protein kinases and phosphatases are the triggers for the induction of LTP/LTD. As calcium influx through the n-methyl-d-aspartate (NMDA) receptor plays a fundamental role in the induction of LTP/LTD, changes in the properties of NMDA receptor-mediated calcium influx will dramatically affect activity-dependent synaptic plasticity (metaplasticity). We demonstrate that experimentally observed metaplasticity can be accounted for by activity-dependent regulation of NMDA receptor subunit composition and function. Our model produces a frequency-dependent LTP/LTD curve with a sliding synaptic modification threshold similar to what has been proposed theoretically by Bienenstock, Cooper, and Munro and observed experimentally.

Footnotes

↵ ‖ To whom reprint requests should be addressed. E-mail: hzs{at}cns.brown.edu.
↵ ** Note that τ_f, the decay time constant of the NMDA heteromers with the NR2A subunit, and τ_2A are different variables.
Abbreviations:

LTP,

long-term synaptic potentiation;

LTD,

long-term synaptic depression;

LFS,

low-frequency stimulation;

AMPA,

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;

AMPAR,

AMPA receptor;

NMDA,

N-methyl-d-aspartate;

NMDAR,

NMDA receptor;

MA,

Mass Action;

MM,

Michaelis–Menten