Brain insulin resistance impairs hippocampal synaptic plasticity and memory by increasing GluA1 palmitoylation through FoxO3a

Matteo Spinelli,Marco Rinaudo,Claudio Grassi,Marco Mainardi,Marcello D’Ascenzo,Francesca Natale,Federico Scala,Alfonso Grassi,Domenica Donatella Li Puma,Salvatore Fusco,Cristian Ripoli,Rosita Lapenta,Andrea Mattera

doi:10.1038/s41467-017-02221-9

Abstract

High-fat diet (HFD) and metabolic diseases cause detrimental effects on hippocampal synaptic plasticity, learning, and memory through molecular mechanisms still poorly understood. Here, we demonstrate that HFD increases palmitic acid deposition in the hippocampus and induces hippocampal insulin resistance leading to FoxO3a-mediated overexpression of the palmitoyltransferase zDHHC3. The excess of palmitic acid along with higher zDHHC3 levels causes hyper-palmitoylation of AMPA glutamate receptor subunit GluA1, hindering its activity-dependent trafficking to the plasma membrane. Accordingly, AMPAR current amplitudes and, more importantly, their potentiation underlying synaptic plasticity were inhibited, as well as hippocampal-dependent memory. Hippocampus-specific silencing of Zdhhc3 and, interestingly enough, intranasal injection of the palmitoyltransferase inhibitor, 2-bromopalmitate, counteract GluA1 hyper-palmitoylation and restore synaptic plasticity and memory in HFD mice. Our data reveal a key role of FoxO3a/Zdhhc3/GluA1 axis in the HFD-dependent impairment of cognitive function and identify a novel mechanism underlying the cross talk between metabolic and cognitive disorders.

Highlights

High-fat diet (HFD) and metabolic diseases cause detrimental effects on hippocampal synaptic plasticity, learning, and memory through molecular mechanisms still poorly understood
To investigate the mechanism underlying the impairment of hippocampal synaptic plasticity in HFD mice and to determine the role of hippocampal insulin signaling in these alterations, we performed electrophysiological, behavioral, and metabolic analyses in C57BL/6 mice after 6 weeks of HFD or standard diet (SD)
In a first cohort of mice, we found that long-term potentiation (LTP) induced at the CA3-CA1 hippocampal synapses by high-frequency stimulation (HFS) was significantly reduced in slices from HFD mice (33.5 ± 6.4% vs. 81.3 ± 6.6%; Fig. 1a)

Summary

Introduction

High-fat diet (HFD) and metabolic diseases cause detrimental effects on hippocampal synaptic plasticity, learning, and memory through molecular mechanisms still poorly understood. Activity-dependent functional plasticity causes structural changes that are essential for the acquisition of new information[2] This is well exemplified by the long-term potentiation (LTP) paradigm, a cellular correlate of learning and memory[3], in which glutamate released following high-frequency stimulation of presynaptic terminals induces N-methyl-D-aspartate (NMDA) receptor/CaMKII signaling activation and recruitment of αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at the postsynaptic site, thereby enhancing the amplitude of excitatory postsynaptic currents (EPSCs)[4]. High-fat diet (HFD) is the most commonly used experimental model of metabolic disease, causing both peripheral insulin resistance and detrimental effects on brain function[14], but the molecular mechanisms underlying the impact of nutrient excess on cognitive function are still poorly understood. No information is available on whether: (i) HFD affects synaptic protein palmitoylation and (ii) this molecular mechanism underlies cognitive function alterations associated with brain insulin resistance

Methods

Results

Conclusion