Resveratrol up-regulates AMPA receptor expression via AMP-activated protein kinase-mediated protein translation

Abstract

Resveratrol is a phytoalexin that confers overall health benefits including positive regulation in brain function such as learning and cognition. However, whether and how resveratrol affects synaptic activity remains largely unknown. α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are glutamatergic receptors that mediate the majority of fast excitatory transmission and synaptic plasticity, and thus play a critical role in higher brain functions, including learning and memory. We find that in rat primary neurons, resveratrol can rapidly increase AMPAR protein level, AMPAR synaptic accumulation and the strength of excitatory synaptic transmission. The resveratrol effect on AMPAR protein expression is independent of sirtuin 1 (SIRT1), the conventional downstream target of resveratrol, but rather is mediated by AMP-activated protein kinase (AMPK) and subsequent downstream phosphoinositide 3-kinase (PI3K)/Akt signaling. Application of the AMPK specific activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) mimics the effects of resveratrol on both signaling and AMPAR expression. The resveratrol-induced increase in AMPAR expression results from elevated protein synthesis via regulation of the eukaryotic initiation factor (eIF) 4E/4G complex. Disruption of the translation initiation complex completely blocks resveratrol-dependent AMPAR up-regulation. These findings indicate that resveratrol may regulate brain function through facilitation of AMPAR biogenesis and synaptic transmission.

Novel Regulation of the Synthesis of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Subunit GluA1 by Carnitine Palmitoyltransferase 1C (CPT1C) in the Hippocampus

“…The fact that we do not observe a complete loss of AMPARs in CPT1C KO neurons highlights the role of other mechanisms involved in AMPAR translation, such as the regulation of initiation and elongation by CPEB3 (35) or the control of expression by miRNA501-3p (36). Recently, it has been demonstrated that the activation of the energy sensor AMPK is involved in GluA1 translation (26). In our model, we observe a strong decrease in the phosphorylation of this kinase in CPT1C KO neurons.…”

“…Recently, it has also been described that phosphorylation of AMPK triggers GluA1 translation (26). Interestingly, CPT1C KO neurons show a reduction in the phosphorylation of this kinase under basal conditions (1.00 Ϯ 0.07 for WT versus 0.41 Ϯ 0.04 for KO; n ϭ 8; p Ͻ 0.001; t test; Fig.…”

Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes

“…This is of particular interest for resveratrol supplementation as knowledge was limited on its ability to modulate glutamatergic transmission and further supports the investigation of resveratrol in the treatment of various aging-related central nervous system disorders. Interestingly, this resveratrol effect has been confirmed independently in rats (Wang et al 2015).…”

Crucial Roles for SIRT2 and AMPA Receptor Acetylation in Synaptic Plasticity and Memory

“…Primary rat (Sprague Dawley) cortical and hippocampal neuron cultures were prepared as described previously (Wang et al, 2015). Briefly, cortices and hippocampi were dissected out from embryonic day 18 (E18) rats of either sex, then digested with papain (0.5 mg/ml in EBSS) and plated on poly-L-lysine coated coverslips or Petri dishes.…”