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

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, Claudio Grassi

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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.

Original languageEnglish
Article number2009
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2017

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Spinelli, M., Fusco, S., Mainardi, M., Scala, F., Natale, F., Lapenta, R., Mattera, A., Rinaudo, M., Li Puma, D. D., Ripoli, C., Grassi, A., D'Ascenzo, M., & Grassi, C. (2017). Brain insulin resistance impairs hippocampal synaptic plasticity and memory by increasing GluA1 palmitoylation through. Nature Communications, 8(1), [2009]. https://doi.org/10.1038/s41467-017-02221-9