Non-scaling regulation of AMPA receptors in homeostatic synaptic plasticity

Abstract

Homeostatic synaptic plasticity (HSP) as an activity-dependent negative feedback regulation of synaptic strength plays important roles in the maintenance of neuronal and neural circuitry stability. A primary cellular substrate for HSP expression is alterations in synaptic accumulation of glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). It is widely believed that during HSP, AMPAR accumulation changes with the same proportion at each synapse of a neuron, a process known as synaptic scaling. However, direct evidence on AMPAR synaptic scaling remains largely lacking. Here we report a direct examination of inactivity-induced homeostatic scaling of AMPAR at individual synapse by live-imaging. Surprisingly, instead of uniform up-scaling, a scattered pattern of changes in synaptic AMPAR was observed in cultured rat hippocampal neurons. While the majority of synapses showed up-regulation after activity inhibition, a reduction of AMPAR could be detected in certain synapses. More importantly, among the up-regulated synapses, a wide range of AMPAR changes was observed in synapses of the same neuron. We also found that synapses with higher levels of pre-existing AMPAR tend to be up-regulated by lesser extents, whereas the locations of synapses relative to the soma seem not affecting AMPAR scaling strengths. In addition, we observed strong competition between neighboring synapses during HSP. These results reveal that synaptic AMPAR may not be scaled during HSP, suggesting novel molecular mechanisms for information processing and storage at synapses.

Keywords: AMPA receptor; AMPAR live-imaging; Homeostatic synaptic plasticity (HSP); Non-scaling regulation; Synaptic scaling.