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

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.

De‐palmitoylation by N‐(tert‐Butyl) hydroxylamine inhibits AMPAR‐mediated synaptic transmission via affecting receptor distribution in postsynaptic densities

“…Under the pathological condition, the increased PAT activity may promote the effect of 2‐BP. Thus, it has been reported that 2‐BP reverts GluA1 hyper‐palmitoylation in the rats treated by high‐fat diet or cocaine exposure . Different from 2‐BP, the direct de‐palmitoylation by NtBuHA is not dependent on PATs.…”

“…Many evidence indicates that aberrant palmitoylation signaling leads to pathology . Thus, pharmacological inhibition of palmitoylation may be potentially used as in the treatment of diseases associated with aberrant palmitoylation signaling, such as human cancer, INCL, brain insulin resistance, and cocaine addiction As a hydroxylamine derivative that mimics palmitoyl‐protein thioesterase, the unique medical value of NtBuHA is to treat INCL (Batten disease), a devastating neurodegenerative lysosomal storage disease caused by mutations in the gene encoding palmitoyl‐protein thioesterase‐1. Here, we observed that palmitoylation‐deficient state initiated by NtBuHA preferentially inhibited AMPAR function.…”

“…Aberrant protein palmitoylation signaling may be implicated in the pathogenesis of various diseases, including human cancer, infantile neuronal ceroid lipofuscinosis (INCL), and brain insulin resistance. [19][20][21][22][23] Emerging evidence shows that palmitoylation of AMPARs is sensitive to psychostimulants such as cocaine, 24 which may control psychomotor sensitivity to the psychostimulants. Thus, pharmacological initiation of palmitoylation-deficient state may potentially be used for drug addiction.…”

“…For the lack in the knowledge about depalmitoylases for AMPAR and its binding partners, 2-bromopalmitate (2-BP), the broad-spectrum palmitoylation inhibitor, has been widely used to investigate the effect of de-palmitoylation via downregulating the palmitoylated protein level. 21,[27][28][29][30][31] Interestingly, the effect of 2-BP on the AMPAR function seems contradictory. It has been reported that 2-BP attenuates AMPAR-activated Ca 2+ signaling and cytotoxicity in motor neurons.…”

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

“…Insulin signalling has also been shown to contribute to synaptogenesis and synaptic remodeling in the rat brain and cultured hippocampal neurons [59], two mechanisms essential for neuronal plasticity. Recently, an interesting study has shown that brain insulin-resistance induced by high-fat diet impairs memory and underlying synaptic plasticity through hyperpalmitoylation of AMPA glutamate receptor subunit GluA1 [60], indicating that intact insulin signalling is required for memory formation. Besides experimental models, in humans, intranasal insulin has been shown to improve memory functions in healthy subjects [61, 62], with no effect on word recall and non-declarative memory but rather on declarative, hippocampus-dependent memory contents [62, 63].…”