Role of perinatal long-chain omega-3 fatty acids in cortical circuit maturation: Mechanisms and implications for psychopathology

Abstract

Accumulating translational evidence suggests that the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) plays a role in the maturation and stability of cortical circuits that are impaired in different recurrent psychiatric disorders. Specifically, rodent and cell culture studies find that DHA preferentially accumulates in synaptic and growth cone membranes and promotes neurite outgrowth, dendritic spine stability, and synaptogenesis. Additional evidence suggests that DHA may play a role in microglia-mediated synaptic pruning, as well as myelin development and resilience. In non-human primates n-3 fatty acid insufficiency during perinatal development leads to widespread deficits in functional connectivity in adult frontal cortical networks compared to primates raised on DHA-fortified diet. Preterm delivery in non-human primates and humans is associated with early deficits in cortical DHA accrual. Human preterm birth is associated with long-standing deficits in myelin integrity and cortical circuit connectivity and increased risk for attention deficit/hyperactivity disorder (ADHD), mood, and psychotic disorders. In general, ADHD and mood and psychotic disorders initially emerge during rapid periods of cortical circuit maturation and are characterized by DHA deficits, myelin pathology, and impaired cortical circuit connectivity. Together these associations suggest that early and uncorrected deficits in fetal brain DHA accrual may represent a modifiable risk factor for cortical circuit maturation deficits in psychiatric disorders, and could therefore have significant implications for informing early intervention and prevention strategies.

Keywords: Amygdala; Attention deficit/hyperactivity disorder; Bipolar disorder; Brain development; Cognition; Connectivity; Docosahexaenoic acid; Mood; Omega-3 fatty acids; Prefrontal cortex; Schizophrenia.

Figure 1

Potential ultrastructural mechanisms by which membrane DHA deficits could lead to a loss in synaptic connectivity. A: Under normal physiological conditions, synaptic membrane phosphatidylserine (gray circles) bind MARCKS (black circles) at the membrane which also cross-links and tethers F-actin to support dendritic spine cytoskeletal structural stability. Binding of MARCKS with membrane phosphatidylserine also inhibits phospholipase Cβ₁-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂) into diacylglycerol (DAG) which increases PKC activity. PKC-mediated phosphorylation of MARCKS reduces the tensile strength of the F-actin cytoskeleton leading to the eventual collapse of the spine; B: Under conditions of membrane DHA deficits, reductions in membrane phosphatidylserine and membrane-bound MARCKS increase PKC activity and destabilizes the F-actin cytoskeleton leading to spine collapse. Elevated PKC activity secondary to membrane DHA deficits may also reduce the resilience of dendritic spines to other pathophysiological factors including chronic stress or inflammation. DHA: Docosahexaenoic acid; PKC: Protein kinase C; MARCKS: Myristoylated alanine-rich C kinase substrate.

Figure 2

Diagram illustrating connectivity between frontal lobe regions, including the dorsolateral prefrontal cortex (Brodmann area 9, BA9,) and orbitofrontal cortex (BA11) which regulate attention and executive function, and temporal lobe structures including the amygdala and hippocampus which regulate mood and memory. Frontal lobe connectivity with limbic structures is mediated in part by the uncinate fasciculus and superior longitudinal fasciculus which develop during gestation and undergo significant maturation during childhood and adolescence. Reduced frontal circuit connectivity is exhibited by DHA-deficient non-human primates, children and adolescents born preterm, and patients with psychiatric disorders including ADHD and bipolar disorder which are associated with DHA deficits. DHA: Docosahexaenoic acid; ADHD: Attention deficit/hyperactivity disorder.

Figure 3

Mean concentrations of choline (Ch), N-acetyl aspartate (NAA), glutamate+ glutamine (Glx), creatine (Cr), and myo-inositol (mI) in the right dorsolateral PFC (A), left dorsolateral PFC (B), and anterior cingulate cortex (C) of children breastfed for < 12 mo (n = 22) or ≥ 12 mo (n = 16). Note that NAA concentrations are significantly greater in the right dorsolateral PFC and anterior cingulate cortex of children breastfed for ≥ 12 mo vs < 12 mo. Values are group means ± SEM. PFC: Prefrontal cortex.

Figure 4

Diagram illustrating a hypothetical role of LCn-3 fatty acid deficiency in the familial transmission of psychopathology. Adolescent and young adult females with mood disorders exhibit significant blood DHA deficits leading to reduced fetal (cord blood) DHA accrual during pregnancy. Low maternal DHA status during pregnancy also increases risk for preterm delivery due in part to elevated pro-inflammatory cytokine levels, as well as low breast milk DHA levels postpartum. Uncorrected deficits in fetal brain DHA accrual lead to long-standing deficits in white matter resilience and integrity and reduced functional connectivity in fronto-striatal circuits and increase risk of developing ADHD symptoms in childhood. Deficits in white matter integrity and reduced functional connectivity in fronto-limbic circuits during adolescent development is associated with the emergence of emotional and/or thought dysregulation and the onset of mood and/or psychotic symptoms. DHA: Docosahexaenoic acid; ADHD: Attention deficit/hyperactivity disorder.