Prostaglandins, Leukotrienes and Essential Fatty Acids
Role of omega-3 fatty acids in brain development and function: Potential implications for the pathogenesis and prevention of psychopathology
Introduction
Because mammals lack the capacity to introduce double bonds at the omega or n-6 and omega or n-3 positions from the carbonyl end of oleic acid, they are dependent on dietary sources of linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3), respectively, to meet their physiological needs for these families of fatty acids. Good dietary sources of ALA include flaxseed, linseed, canola, soy, and perilla oils. The principle omega-3 fatty acid metabolites of ALA are eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). DHA synthesis from dietary ALA is limited in humans [1], [2], [3], [4]. However, preformed DHA and EPA can be obtained directly from the diet, particularly fatty fish, e.g., salmon, trout, and tuna. Dietary DHA is significantly more effective than is dietary ALA as a source for DHA accrual in the developing human [5], [6], [7], primate [8], and rat brain [9], as well as in the adult rat brain [10].
Mammalian brain tissue is predominantly composed of lipids which are comprised of different saturated, monounsaturated, and polyunsaturated fatty acids (Fig. 1). The principle omega-3 fatty acid found in brain is DHA, comprising 10–20% of total fatty acids composition, whereas the omega-3 fatty acids ALA, EPA, and docosapentaenoic acid (22:5n-3) comprise <1% of total brain fatty acid composition. The ratio of saturated, monounsaturated, and polyunsaturated fatty acids observed in postmortem human frontal cortex is generally conserved among other mammals, including monkeys [11], rats [12], and mice [13]. For example, adult rodents/primates maintained on a diet containing ALA exhibit frontal cortex DHA concentrations of ∼20% of total fatty acids. Studies in adult rodents and primates also demonstrate that DHA concentrations differ between brain regions. In rodents, DHA is most concentrated in the frontal cortex and hippocampus (16–22% of total fatty acids) and less concentrated in the striatum (∼14% of total fatty acids), midbrain (∼13% of total fatty acids), and pons/medulla (∼10% of total fatty acids) [13], [14], [15], [16], [17]. In the neonatal baboon brain, the highest DHA concentrations are in the globus pallidus, superior colliculus, putamen and precentralis regions (14% of total fatty acids), followed by cortical regions, including the frontal cortex (12.9% of total fatty acids) [18].
Within brain tissues, DHA preferentially accumulates in growth cones, synaptosomes, astrocytes, myelin, microsomal, and mitochondrial membranes [19], [20], [21], [22], [23], [24]. DHA is predominantly acetylated into the sn-2 position of the phospholipids phosphatidylethanolamine and phosphatidylserine, and saturated fatty acids, predominantly stearic acid or palmitic acid, occupy the sn-1 position [25]. Fatty acids are mobilized from membrane phospholipids by PLA2-mediated hydrolyses of the acyl ester bond. The calcium-independent iPLA2 and PlsEtn-PLA2 isoforms mobilize DHA, and the calcium-dependent cPLA2 isoform preferentially mobilizes the omega-6 fatty acid arachidonic acid [26]. Once mobilized, DHA may act as a second messenger in the modulation of synaptic signal transduction pathways [27], is metabolized into anti-inflammatory docosanoids [28], is degraded by β-oxidation or peroxidation [29], or is reacylated into membrane phospholipids by aceyltransferases. It has been estimated that approximately 2–8% of brain DHA is replaced daily due to metabolism, and DHA has a loss half-life in total brain phospholipids of 33 days under steady-state ALA intake [30], [31].
The dynamics associated with brain DHA accrual during perinatal development, and the consequences of deficits in perinatal brain DHA accrual on brain maturation and function, have been most extensively characterized in rodents, and preliminarily characterized in nonhuman primates and humans.
Section snippets
Brain DHA accrual during perinatal brain development
Under conditions of maternal dietary ALA and/or DHA exposure during perinatal rat brain development, DHA concentrations increase sharply between embryonic day 14 and birth (embryonic day 21) to constitute 10–12% of total fatty acids. Postnatally, DHA concentrations continue to increase to plateau on postnatal day 21 at approximately 10–20% of total fatty acids [32], [33], [34]. This perinatal increase in cortical DHA concentrations coincides with active periods of neurogenesis, neuroblast
Brain DHA accrual during perinatal brain development
In the developing primate (monkey) brain, frontal cortex DHA concentrations at birth represent ∼15% of total fatty acids, and between birth and 22 months of age, increase to comprise ∼22% of total fatty acids [11], [97]. Primates (baboon) born preterm (gestation week 22 vs. term—gestation week 26) exhibit significantly lower (22–35%) postmortem brain DHA concentrations relative to term-born primates [98], [99]. These findings indicate that in primates brain DHA accrual occurs predominantly
Brain DHA accrual during perinatal brain development
DHA accumulates in human brain tissue at a rapid rate (∼14.5 mg/week) during the third trimester (gestational weeks 26–40) [106], [107]. At term birth, DHA represents approximately 9% of total cortical fatty acid composition, and increases by an additional ∼6% between birth and age 20 to compose ∼15% total cortical fatty acid composition in postmortem brain tissue from subjects residing in the US at time of death [108]. Infants born preterm (<33 weeks of gestation) exhibit lower (−40%)
Summary and conclusions
There is now good evidence suggesting that DHA is accrued in rodent, primate, and human brain during active periods of perinatal cortical maturation, and that DHA plays an important role in neuronal differentiation, synaptogenesis, and synaptic function. In animal studies, prenatal deficits in brain DHA accrual that are not corrected via postnatal dietary fortification are associated with enduring deficits in neuronal arborization, multiple indices of synaptic pathology, deficits in
Acknowledgements
This work was supported in part by NIH/NIMH grants MH073704 and MH074858 (R.K.M.).
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