How to Scale Down Postsynaptic Strength

Synaptic scaling is a form of synaptic plasticity that contributes to the homeostatic regulation of neuronal activity both in vitro and in vivo, by bidirectionally and proportionally adjusting postsynaptic AMPA receptor (AMPAR) abundance to compensate for chronic perturbations in activity. This proportional regulation of synaptic strength allows synaptic scaling to normalize activity without disrupting the synapse-specific differences in strength thought to underlie memory storage, but how such proportional scaling of synaptic strength is accomplished at the biophysical level is unknown. Here we addressed this question in cultured rat visual cortical pyramidal neurons. We used photoactivation and fluorescence recovery after photobleaching of fluorescently tagged AMPAR to show that scaling down, but not up, decreases the steady-state accumulation of synaptic AMPAR by increasing the rate at which they unbind from and exit the postsynaptic density (Koff). This increase in Koff was not diffusion limited, was independent of AMPAR endocytosis, and was prevented by a scaffold manipulation that specifically blocks scaling down, suggesting that it is accomplished through enhanced dissociation of AMPAR from synaptic scaffold tethers. Finally, simulations show that increasing Koff decreases synaptic strength multiplicatively, by reducing the fractional occupancy of available scaffold slots. These data demonstrate that scaling down is accomplished through a regulated increase in Koff, which in turn reduces the fractional occupancy of synaptic scaffolds to proportionally reduce synaptic strength.