δ-Tocotrienol Increases Hippocampal Network Excitability Through Upregulation of GluA1-Containing AMPA Receptors

Abstract

Abstract Objectives A common feature of aging and several neurological diseases including Alzheimer's disease is the downregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which results in a decrease in excitatory neurotransmission. Tocotrienols, vitamin E with an isoprenoid side chain, have been shown to suppress inflammation and the prenylation of proteins that regulate neuronal functions. Accumulating evidence suggests that tocotrienols may promote cognitive improvement in hippocampal-dependent learning tasks. We hypothesized that tocotrienols could promote cognitive improvement via increasing excitatory synaptic transmission. Methods To test our hypothesis, we measured surface levels of GluA1 in cultured primary hippocampal neurons from postnatal mice treated with 1 μmol/L δ-tocotrienol using an on-cell western blot. Aβ40 and Aβ42 secreted in the media were quantified using an ELISA-based assay. Alterations in excitatory synaptic transmission induced by δ-tocotrienol were confirmed by performing whole cell voltage patch clamp recordings of spontaneous excitatory postsynaptic currents (sEPSC) in primary cultured hippocampal neurons. Results Surface GluA1 was increased after 24 hours of treatment with 1 μmol/L δ-tocotrienol. δ-Tocotrienol (1 μmol/L) also significantly decreased the level of Aβ40 and Aβ42 in hippocampal culture media. Moreover, a significant increase was observed in sEPSC amplitudes but not sEPSC frequency in neurons treated with δ-tocotrienol. Conclusions δ-Tocotrienol promotes cognitive improvement via increases in AMPA receptor mediated neurotransmission and may be beneficial in restoring early stage excitatory synaptic dysfunction in aging and neurological disease. Funding Sources American River Nutrition Inc. and the Whitehall Foundation (Grant 2017–05-35).