Abstract
Regulation of AMPA receptor expression by neuronal activity and neuromodulators is critical to the expression of both long-term potentiation (LTP) and memory. In particular, Ca2+-permeable AMPARs (CP-AMPAR) play a unique role in these processes due to their transient, activity-regulated expression at synapses. Secreted amyloid precursor protein-alpha (sAPP alpha), a metabolite of the parent amyloid precursor protein (APP) has been previously shown to enhance hippocampal LTP as well as memory formation in both normal animals and in Alzheimer's disease models. In earlier work we showed that sAPP alpha promotes trafficking of GluA1-containing AMPARs to the cell surface and specifically enhances synthesis of GluA1. To date it is not known whether de novo synthesized GluA1 form CP-AMPARs or how they contribute to sAPP alpha-mediated plasticity. Here, using fluorescent non-canonical amino acid tagging-proximity ligation assay (FUNCAT-PLA), we show that brief treatment of primary rat hippocampal neurons with sAPP alpha (1 nM, 30 min) rapidly enhanced the cell-surface expression of de novo GluA1 homomers and reduced levels of de novo GluA2, as well as extant GluA2/3-AMPARs. The de novo GluA1-containing AMPARs were localized to extrasynaptic sites and later internalized by sAPP alpha-driven expression of the activity-regulated cytoskeletal-associated protein, Arc. Interestingly, longer exposure to sAPP alpha increased synaptic levels of GluA1/2 AMPARs. Moreover, the sAPP alpha-mediated enhancement of LTP in area CA1 of acute hippocampal slices was dependent on CP-AMPARs. Together, these findings show that sAPP alpha engages mechanisms which specifically enhance the synthesis and cell-surface expression of GluA1 homomers, underpinning the sAPP alpha-driven enhancement of synaptic plasticity in the hippocampus.