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

Matteo Spinelli, Salvatore Fusco (), Marco Mainardi, Federico Scala, Francesca Natale, Rosita Lapenta, Andrea Mattera, Marco Rinaudo, Domenica Donatella Li Puma, Cristian Ripoli, Alfonso Grassi, Marcello D’Ascenzo and Claudio Grassi
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Matteo Spinelli: Università Cattolica Medical School
Salvatore Fusco: Università Cattolica Medical School
Marco Mainardi: Università Cattolica Medical School
Federico Scala: Università Cattolica Medical School
Francesca Natale: Università Cattolica Medical School
Rosita Lapenta: University of Salerno
Andrea Mattera: Università Cattolica Medical School
Marco Rinaudo: Università Cattolica Medical School
Domenica Donatella Li Puma: Università Cattolica Medical School
Cristian Ripoli: Università Cattolica Medical School
Alfonso Grassi: University of Salerno
Marcello D’Ascenzo: Università Cattolica Medical School
Claudio Grassi: Università Cattolica Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02221-9

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