Effect of membrane fluidity on brain receptors and transporters

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The objective of this research program in neuropharmacology is to investigate the effect of membrane composition/fluidity on neurotransmitter function in the brain. The hypothesis is that changes of membrane composition and/or fluidity will have effects specific for certain receptors and transporters and specific for certain brain regions. We propose to investigate in vitro a dose-response of agents that rigidify membranes (cholesteryl hemisuccinate and stearic acid) compared to agents that fluidify membranes (linoleic acid, L-alpha-phosphatidylcholine and DHA, omega-3, a widely used nutritional supplement) in bovine brain membranes. We will investigate how fluidity changes affect dopamine (D2), adenosine (A2A), GABAA, serotonin (5-HT1A, 5-HT2A) glutamate (NMDA, mGluR5) receptors compared to the dopamine transporter DAT. The frontal cortex, the hippocampus and the striatum representing a range from more fluid to more rigid brain membranes will be studied. Fluidity will be measured with fluorescent probes. Total membrane receptors and transporters will be measured by Western blot and their surface levels with binding of specific radioligands. The functional changes will be measured with coupling to second messengers and key signaling proteins. In vivo in rats a condition presenting a more rigid membrane will be investigated with old rat whereas more fluid membranes will be investigated by reducing cholesterol with a chronic statin drug treatment, DHA treatment or plasmalogen (to increase DHA levels) treatment. For in vivo experiments we will also measure by in situ hydridization mRNA of these receptors to assess their synthesis. We expect that small membrane changes will significantly affect the membrane receptor investigated and that this has important physiological consequences. Compounds affecting membranes could be administered (or a diet designed) to enhance efficacy of drug treatments targeting these receptors and transporters for successful aging.