GENETIC DEFICIENCY IN THE SEROTONIN REUPTAKE TRANSPORTER INCREASES BRAIN ARACHIDONIC ACID METABOLISM. Humans carrying the short (S) compared with long (L) allele of the presynaptic serotonin reuptake transporter (5-HTT) promoter have increased brain extracellular serotonin (5-HT) and are at increased risk for neuropsychiatric disease. The heterozygous 5-HTT-knockout mouse (5-HTT-/+) also has elevated synaptic 5-HT and shows depressive-like behaviors, and is considered a model for humans carrying the S allele. Using our in vivo imaging with quantitative autoradiography, we demonstrated 20-70% greater arachidonic acid (AA) incorporation from plasma into the brain of the 5-HTT-/+ mouse than of the wild type 5-HTT+/+ mouse. The 5-HTT-/+ mouse also had an elevated activity of brain cytosolic phospholipase A2, which releases AA from membrane phospholipid and is coupled to post-synaptic 5-HT2A/2C receptors. Our finding that reduced 5-HTT function during neurodevelopment increased brain AA signaling in the mouse suggests that AA signaling also would be elevated in humans with the S compared with L promoter allele;this can be tested in the clinic using positron emission tomography (PET) (Basselin et al., 2009) WHY MAY ALZHEIMER DISEASE PATIENTS NOT RESPOND TO CHRONIC CHOLINESTERASE INHIBITION? Memory changes in Alzheimer disease have been ascribed to defective cholinergic transmission. Donepezil, an acetylcholinesterase inhibitor is used to treat the disease, is thought to act by increasing synaptic acetylcholine, thus stimulating post-synaptic muscarinic receptors that are coupled to cytosolic phospholipase A2 (cPLA2) and arachidonic acid (AA) release from membrane phospholipid. However, some clinical trials indicate no significant Donepezil effect. We found that the AA signaling response to Donepezil in unanesthetized rats showed desensitization (the response was present following acute but not chronic donepezil), which may explain the negative clinical results (Basselin et al., 2009). TOLERANCE TO NICOTINE. Nicotine can improve memory and attention, but also is addictive. In brain, nicotine binds primarily to high-affinity presynaptic alpha4beta2 receptors, which modulate release of other neurotransmitters that can activate post-synaptic receptors coupled to cytoplasmic phospholipase A2, to release arachidonic acid (AA) from membrane phospholipid. Using our in vivo fatty acid method, we reported that nicotine at a dose equivalent to smoking 1 cigarette (0.1 mg/kg, s.c.), compared to saline, decreased the AA signal in rat brain at 2 min but not at 10 min after injection, consistent with rapid desensitization reported for alpha4beta2 receptors. The 2-min AA signal was blocked by the alpha4beta2 antagonist mecamylamine. Desensitization of the AA signal, confirmed in this study, may play a role in nicotine addiction and explain inefficacy of cholinergic therapy in Alzheimer Disease (Chang et al., 2009) THE ROLE OF CALCIUM INDEPENDENT PHOSPHOLIPASE A2 IN BRAIN Studies suggest that arachidonic acid (AA) and docosahexaenoic acid (DHA) are hydrolyzed from synaptic membrane phospholipids by calcium-dependent cytosolic phospholipase A2 (cPLA2) and calcium-independent iPLA2, respectively. In a critical review, we presented a model in which neurotransmitters regulate the activity of these enzymes and thus the balanced and localized release of AA and DHA from phospholipid in the brain, depending on the primary source (intracellular or extracellular) of the calcium signal (Rosa et al., 2009). EXTRACELLULAR-DERIVED CALCIUM DOES NOT INITIATE NEUROTRANSMISSION VIA DOCOSAHEXAENOIC ACID. Docosahexaenoic acid (DHA, 22:6n-3) is found in high concentrations in brain synapses, but its role as a signaling molecule is uncertain. In vitro studies show that DHA can be released from membrane phospholipid by calcium-independent phospholipase A2, iPLA2, but not by calcium-dependent cytosolic cPLA2, which selectively releases arachidonic acid (AA). Since glutamatergic N-methyl-D-aspartate (NMDA) receptor activation allows extracellular calcium into cells, we hypothesized that brain AA but not DHA signaling would be increased in rats given NMDA. We confirmed this hypothesis using quantitative autoradiography. Greater AA than DHA release during excess glutamate stimulation of NMDA receptors could contribute to excitotoxic brain damage (Ramadan et al., 2010). ALTERED BRAIN DOCOSAHEXAENOIC ACID METABOLISM AND SIGNALING IN iPLA2-DEFICIENT MICE. Calcium-independent phospholipase A2beta (iPLA2beta) selectively hydrolyzes docosahexaenoic acid (DHA, 22:6n-3) from phospholipid. Mutations in the PLA2G6 gene encoding this enzyme occur in patients with neurological disorders including Parkinson disease, and mice lacking PLA2G6 show neurological dysfunction and neuropathology after 13 months. We demonstrated that brain DHA metabolism and cholinergic receptor mediated DHA-signaling were reduced in 4-month-old iPLA2beta-deficient mice before overt neuropathology, using our in vivo imaging technique. Thus, iPLA2beta is critical for maintaining normal brain DHA metabolism in the intact organism. Positron emission tomography (PET) would be expected to show disturbed brain DHA metabolism in patients with PLA2G6 mutations, and treatment with elevated dietary DHA may be helpful in such patients (Basselin et al., 2010).
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