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glutamate receptor trafficking; hippocampus; metaplasticity; protein synthesis; secreted amyloid precursor protein-alpha;synaptic plasticity
Abstract:
Secreted amyloid precursor protein-alpha (sAPP) has growth factor-like properties and can modulate long-term potentiation (LTP)and memory. Here, we demonstrate that exposure to sAPPconverts short-lasting LTP into protein-synthesis-dependent late LTP inhippocampalslicesfrommalerats.sAPPhadnodiscernableeffect.WehypothesizedthatsAPPfacilitatedLTPviaregulatedglutamatereceptor trafficking anddenovoprotein synthesis. We found using a linear mixed model that sAPPstimulated trafficking of GluA2-lacking AMPARs, as well as NMDARs to the extrasynaptic cell surface, in a calcium/calmodulin-dependent kinase II and protein kinaseG-dependent manner. Both cell surface receptor accumulation and LTP facilitation were present even after sAPPwashout and inhibi-tion ofreceptor trafficking or protein synthesis prevented all these effects. Direct visualization of newly synthesized proteins (FUNCAT-PLA)confirmed the ability of sAPPto stimulatedenovoprotein synthesis and revealed GluA1 as one of the upregulated proteins. Therefore, sAPPgenerates a coordinated synthesis and trafficking of glutamate receptors to the cell surface that facilitate LTP
