Homeostatic regulation of AMPA receptor trafficking and degradation by light-controlled single-synaptic activation

During homeostatic adjustment in response to alterations in neuronal activity, synaptic expression of AMPA receptors (AMPARs) is globally tuned up or down so that the neuronal activity is restored to a physiological range. Given that a central neuron receives multiple presynaptic inputs, whether and how AMPAR synaptic expression is homeostatically regulated at individual synapses remain unclear. In cultured hippocampal neurons we report that when activity of an individual presynaptic terminal is selectively elevated by light-controlled excitation, AMPAR abundance at the excited synapses is selectively downregulated in an NMDAR-dependent manner. The reduction in surface AMPARs is accompanied by enhanced receptor endocytosis and dependent on proteasomal activity. Synaptic activation also leads to a site-specific increase in the ubiquitin ligase Nedd4 and polyubiquitination levels, consistent with AMPAR ubiquitination and degradation in the spine. These results indicate that AMPAR accumulation at individual synapses is subject to autonomous homeostatic regulation in response to synaptic activity.