Secreted Amyloid Precursor Protein-Alpha Enhances LTP Through the Synthesis and Trafficking of Ca2+-Permeable AMPA Receptors

Rhys W Livingstone,Joanna M Williams,Courteney M Westlake,Anurag Singh,Megan K Elder,Warren P Tate,Wickliffe C Abraham

doi:10.3389/fnmol.2021.660208

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 (sAPPα), 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 sAPPα 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 sAPPα-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 sAPPα (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 sAPPα-driven expression of the activity-regulated cytoskeletal-associated protein, Arc. Interestingly, longer exposure to sAPPα increased synaptic levels of GluA1/2 AMPARs. Moreover, the sAPPα-mediated enhancement of LTP in area CA1 of acute hippocampal slices was dependent on CP-AMPARs. Together, these findings show that sAPPα engages mechanisms which specifically enhance the synthesis and cell-surface expression of GluA1 homomers, underpinning the sAPPα-driven enhancement of synaptic plasticity in the hippocampus.

Highlights

Dynamic changes in α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor (AMPAR) expression govern neuronal synaptic efficacy, and promote synaptic plasticity
We have shown that sAPPα promotes synaptodendritic protein synthesis (Claasen et al, 2009) and new gene transcription (Ryan et al, 2013), but brings about a protein synthesisdependent trafficking of GluA1-AMPARs to the cell surface (Mockett et al, 2019) and enhances Arc protein expression (Livingstone et al, 2019), yet how these changes contribute to the documented sAPPα-driven enhancement of synaptic plasticity in the hippocampus is unresolved
SAPPα Promotes the Rapid and Transient Trafficking of de novo GluA1-Containing AMPARs to the Somatic and Dendritic Cell Surface. It is not known whether sAPPα induces the rapid synthesis of GluA1-containing AMPARs or whether these de novo molecules are trafficked to the cell surface and contribute to plasticity

Summary

Introduction

Dynamic changes in α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor (AMPAR) expression govern neuronal synaptic efficacy, and promote synaptic plasticity. These changes are thought to underlie information coding and storage in learning and memory processes (Anggono and Huganir, 2012). These processes are driven through the regulated synthesis and trafficking of AMPARs to and from the synapse, under strict, activity-regulated guidance (Rumpel et al, 2005). Evidence for CP-AMPARs has been shown following in vivo learning paradigms (Clem and Barth, 2006; Conrad et al, 2008; Clem and Huganir, 2010; Hong et al, 2013; Zhang et al, 2016; Takemoto et al, 2017; Torquatto et al, 2019) and stimulationevoked synaptic plasticity (Williams et al, 2007), and may arise in response to neuromodulators including serotonin (Jitsuki et al, 2011), nicotine (Tang et al, 2015), dopamine (Bellone and Lüscher, 2006; Gao et al, 2006), norepinephrine (Clem and Huganir, 2013), estrogen (Tada et al, 2013, 2015), tumor necrosis factor-α (Leonoudakis et al, 2008), glycine (Fortin et al, 2010; Jaafari et al, 2012), and brain-derived neurotrophic factor (Li and Keifer, 2009; Fortin et al, 2012)

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