The mevalonate suppressor δ-tocotrienol increases AMPA receptor-mediated neurotransmission

Synaptic dysfunction is a hallmark of aging and is found in several neurological disorders such as Alzheimer's disease. A common mechanism related to synaptic dysfunction is dysregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which mediate excitatory neurotransmission and synaptic plasticity. Accumulating evidence suggests that tocotrienols, vitamin E molecules that contain an isoprenoid side chain, may promote cognitive improvement in hippocampal-dependent learning tasks. Tocotrienols have also been shown to reduce the secretion of β-amyloid (Aβ) and cholesterol biosynthesis in part by downregulating 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that controls flux of the mevalonate pathway and cholesterol biosynthesis. We hypothesized that tocotrienols might promote cognitive improvement by increasing AMPA receptor-mediated synaptic transmission. Here, we found that δ-tocotrienol increased surface levels of GluA1 but not the GluA2 AMPA receptor subunit in primary hippocampal neurons. Unexpectedly, δ-tocotrienol treatment caused a decrease in the phosphorylation of GluA1 at Serine 845 with no significant changes in GluA1 at Serine 831. Moreover, δ-tocotrienol increased spontaneous excitatory postsynaptic current (sEPSC) amplitude and reduced the secretion of Aβ₄₀ in primary hippocampal neurons. Taken together, our findings suggest that δ-tocotrienol increases AMPA receptor-mediated neurotransmission via noncanonical changes in GluA1 phosphorylation status. These findings suggest that δ-tocotrienol may be beneficial in ameliorating synaptic dysfunction found in aging and neurological disease.