FoxO3a/Zdhhc3/AMPA receptor GluR1 cascade at the crossroad between insulin resistance and impairment of synaptic plasticity and memory

High-fat diet (HFD) and metabolic diseases cause detrimental effects on hippocampal synaptic plasticity, learning and memory through molecular mechanisms still poorly understood. Mice fed a HFD for 6 weeks showed reduced long-term potentiation (LTP) at CA3-CA1 synapses (standard diet [SD] = 186.2 ± 19.9%, HFD = 123.6 ± 8.1%; n=9 for each group; p<0.05) and memory deficits evaluated by novel object recognition test (preference index: SD = 67.9 ± 1.8%, HFD = 59.2 ± 1.6%; n=10 for each group; p<0.001) and Morris water maze task (time spent in the target quadrant during the probe test: SD = 34.6 ± 1.3 s, HFD= 21.4 ± 1.3 s; n=8 for each group; p<0.001). HFD mice also exhibited increased palmitic acid deposition in the hippocampus and brain insulin resistance leading to FoxO3a-mediated overexpression of the palmitoyl-transferase Zdhhc3. The excess of palmitic acid along with higher Zdhhc3 levels induced hyper-palmitoylation of AMPA glutamate receptor subunit GluR1 (+30 ± 1%; n=5; p<0.05) and reduced its phosphorylation at serine 845 (-35 ± 1%; n=4; p<0.05). To deeply investigate the molecular mechanism underlying the diet-dependent change of GluR1 palmitoylation we set up an in vitro model resembling the in vivo metabolic stress. Mouse hippocampal neurons treated for 24h with 20 nM insulin and 200 µM palmitic acid (IPA) showed: i) increased GluR1 palmitoylation/S845 phosphorylation ratio; ii) reduced GluR1 trafficking to the plasma membrane and lower binding with PSD-95 (-70 ± 2% of controls; n=4; p<0.01); iii) loss of GluR1 activation upon a chemical LTP protocol. Accordingly, AMPAR current amplitudes and, more importantly, their potentiation underlying synaptic plasticity, were inhibited upon IPA treatment. Strikingly, both hippocampus-specific silencing of ZDHHC3 and intranasal injection of a palmitoyl-transferase inhibitor counteracted GluR1 hyper-palmitoylation and restored synaptic plasticity and memory in HFD mice. Our data reveal a key role of FoxO3a/Zdhhc3/GluR1 axis in the HFD-dependent impairment of cognitive function and identify a novel mechanism underlying the crosstalk between metabolic and cognitive disorders.