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

• DOI: 10.1038/s41467-017-02221-9
• Publication Date: 2017-12-04T14:54:38Z
• Authors: Matteo Spinelli; Salvatore Fusco; Marco Mainardi; Federico Scala; Francesca Natale; Rosita Lapenta; Andrea Mattera; Marco Rinaudo; Domenica Donatell...; Cristian Ripoli; Alfonso Grassi; Marcello D’Ascenzo; Claudio Grassi
• Keywords: Palmitoylation

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