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.

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., Brain insulin resistance impairs hippocampal synaptic plasticity and memory by increasing GluA1 palmitoylation through FoxO3a., <<NATURE COMMUNICATIONS>>, 2017; 8 (1): N/A-N/A. [doi:10.1038/s41467-017-02221-9] [http://hdl.handle.net/10807/110463]

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

Spinelli, M;Fusco, S;Natale, F;Mattera, A;Rinaudo, M;Li Puma DD,;Ripoli, C;D’Ascenzo, M;Grassi, C.
2017

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.
Inglese
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., Brain insulin resistance impairs hippocampal synaptic plasticity and memory by increasing GluA1 palmitoylation through FoxO3a., <>, 2017; 8 (1): N/A-N/A. [doi:10.1038/s41467-017-02221-9] [http://hdl.handle.net/10807/110463]
File in questo prodotto:
File Dimensione Formato  
Nature Commun. 8, 2009, 2017.pdf

accesso aperto

Tipologia file ?: Versione Editoriale (PDF)
Licenza: Creative commons
Dimensione 2.73 MB
Formato Adobe PDF
2.73 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/110463
Citazioni
  • ???jsp.display-item.citation.pmc??? 56
  • Scopus 96
  • ???jsp.display-item.citation.isi??? 96
social impact