Role of omega-3 fatty acids in brain development and function: Potential implications for the pathogenesis and prevention of psychopathology

Abstract

The principle omega-3 fatty acid in brain, docosahexaenoic acid (DHA), accumulates in the brain during perinatal cortical expansion and maturation. Animal studies have demonstrated that reductions in perinatal brain DHA accrual are associated with deficits in neuronal arborization, multiple indices of synaptic pathology including deficits in serotonin and mesocorticolimbic dopamine neurotransmission, neurocognitive deficits, and elevated behavioral indices of anxiety, aggression, and depression. In primates and humans, preterm delivery is associated with deficits in fetal cortical DHA accrual, and children/adolescents born preterm exhibit deficits in cortical gray matter maturation, neurocognitive deficits particularly in the realm of attention, and increased risk for attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. Individuals diagnosed with ADHD or schizophrenia exhibit deficits in cortical gray matter maturation, and medications found to be efficacious in the treatment of these disorders increase cortical and striatal dopamine neurotransmission. These associations in conjunction with intervention trials showing enhanced cortical visual acuity and cognitive outcomes in preterm and term infants fed DHA, suggest that perinatal deficits in brain DHA accrual may represent a preventable neurodevelopmental risk factor for the subsequent emergence 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.