Figure 7.

Model depicting involvement of ubiquitin-dependent AMPAR trafficking in synaptic downscaling. A, AMPAR activation recruits Nedd4-1 to dendritic spines through a mechanism dependent on calcium and the C2 domain, leading to AMPAR internalization. NMDAR activation causes activation of USP8 through dephosphorylation by a protein tyrosine phosphatase (PTP), promoting the recycling of internalized AMPARs. B, Increased synaptic activity through prolonged bicuculline treatment leads to a decrease in USP8 levels and an increase in and recruitment of Nedd4-1 at synapses, causing a shift in the balance of AMPAR trafficking that overall favors their internalization, resulting in downscaling of synaptic strength.