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.
Mixtures of Cp*TiR3 (with Cp* =
C5(CH3)5
and R = CH3, 13CH3) and
equimolar amounts of B(C6F5)3
or
C(C6H5)3B(C6F5)4,
active in the syndiospecific polymerization of styrene, have been investigated by means of
ESR spectroscopy. At room temperature the formation
of Cp*TiR+ complexes has been observed. Rapid
insertion of styrene occurs in Ti−R bonds of these cationic
Ti(III) complexes, strongly suggesting their role in
the
stereospecific polyinsertion.
The reactivity of the alkyl complexes [Cp*Ti(III)(CH3)][RB(C6F5)3] (Cp* ) η 5 -C5Me5; R ) CH3, -C6F5) with R-13 C-enriched p-chlorostyrene has been investigated by means of ESR spectroscopy in order to gain insight into the chemical structure of the active species in syndiospecific polymerization of styrene and substituted styrenes promoted by "half-titanocene"-based catalysts. Secondary (2,1) polyinsertion of p-chlorostyrene into a Ti(III)-alkyl bond has been observed under polymerization conditions. The role of Cp*Ti III R + complexes in syndiospecific styrene polymerization has conclusively been confirmed. Furthermore, the reaction of the 13 C-enriched complex [Cp*Ti( 13 CH3)][RB(C6F5)3] with PMe3 and Al( 13 CH3)3 has also been investigated by ESR spectroscopy. PMe3 displaces the methylborate anion from the coordination sphere of the Cp*Ti 13 CH3(µ-13 CH3)B(C6F5)3 ion pair and produces the corresponding phosphine adduct Cp*Ti(CH3)(PMe3)2 + . In the same manner, the reaction of [Cp*Ti( 13 -CH3)][B(C6F5)4] with Al( 13 CH3)3 affords the [Cp*Ti(µ-13 CH3)3Al( 13 CH3)] + adduct. The increase of the intensity of the Ti(III) signals observed in the ESR spectra of these catalytic systems after addition of the monomer has been explained on the basis of the ESR results reported above.
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