Brain Phospholipid Metabolism, In Relation To Function,

Aging

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Abstract

Lipid metabolism consumes 25% of the brain's ATP. We calculated that brain de novo phospholipid synthesis, fatty acid deacylation-reacylation in phospholipids, phosphatidylinositide (PI) turnover, and maintaining membrane asymmetries of ether phospholipids, consume about 25% of net brain ATP utilization (Purdon and Rapoport In press). Our high estimate supports a very active participation of brain lipids in signaling and other processes.[unreadable] [unreadable] Importance of brain microwaving. Even the few seconds of ischemia during brain removal from an animal markedly disturbs brain lipid composition, including the concentration of anandamide. High energy microwaving provides more accurate measurements (Bazinet et al. 2005c). [unreadable] [unreadable] Phosphatidylinositol (PI) signaling. We developed a method involving long term subcutaneous infusion of myo-[2H6]inositol in awake rats, to estimate changes in specific activities of brain myoinositol and PI, using GC-MS. With this method, we calculated that the half-life of PI in brain of awake rats is less than 12 hours, consistent with its participation in signaling processes (Ma et al. 2006).[unreadable] [unreadable] Current in vivo neuroimaging methods ignore neuroreceptor-initiated signal transduction. We are elaborating methods to measure brain signal transduction involving arachidonic acid (AA).[unreadable] [unreadable] Significance of arachidonic acid signal. Studies in cyclooxygenase (COX)-2 knockout mice compared with wild type littermates showed upregulation of the baseline brain AA incorporation coefficient k*, consistent with upregulated AA metabolizing enzymes of than COX-2, but loss of the signal in response to the cholinergic muscarinic agonist arecoline (Basselin et al. 2006c). The activated signal thus represents AA that is released by phospholipase A2 (PLA2) from membrane phospholipid and then lost to prostaglandin E2 (PGE2) via COX-2. [unreadable] [unreadable] AA signal in serotonin reuptake transporter (SERT) knockout mice knockout mice. Baseline values of k* for AA were elevated in homozygous and heterozygous SERT knockout mice compared with wild type mice, consistent with high levels of synaptic serotonin levels in the knockouts (Qu et al. 2005). [unreadable] [unreadable] Direct and indirect acute dopamine receptor signaling responses to agonists and amphetamine. In awake rats, acute administration of the dopamine D2 receptor agonist quinpirole but not of a D1 receptor agonist increased k* for AA at brain D2-like receptor sites (Bhattacharjee et al. 2005). Acute amphetamine, which increases extracellular dopamine by reversing the direction of the DAT, increased k* solely via D2 receptors, as its increments were blocked by pre-administration of the D2 receptor antagonist, raclopride (Bhattacharjee et al. 2006). [unreadable] [unreadable] Imaging the acute NMDA signal. We imaged significant increments in k* for AA in awake rats given subconvulsant i.p. doses of NMDA, which activates cPLA2 by increased brain Ca2+ concentrations. The increases were blocked by pretreatment with the NMDA antagonist MK-801, or chronic lithium (Basselin et al. 2006b), an effect which may account for some of lithium's efficacy against mania of bipolar disorder. [unreadable] [unreadable] Circulating polyunsaturated fatty acid (PUFA) precursors do not replace the arachidonic acid (AA) or docosahexaenoic acid (DHA) lost by brain metabolism. We showed in that the n-3 PUFA metabolic precursors, circulating linoleic acid (LA) and ?-linolenic acid (?-LNA), did not significantly replace AA or DHA, respectively, metabolized and lost in brain (Demar et al. 2005; Demar et al. In press). [unreadable] [unreadable] One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats. Male rat pups at weaning (21 days of age) that were subjected to a diet deficient in n-3 polyunsaturated fatty acids (n-3 PUFAs) for 15 weeks showed increased scores on tests of depression and aggression, consistent with a report that dietary n-3 PUFAs are effective in bipolar disorder.