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

Core tip: Although the role of perinatal brain omega-3 fatty acid (DHA) accrual on the maturation and long-term stability of cortical circuitry is only beginning to be fully understood, extant translational evidence suggests that DHA plays a role in the initial development and early maturation of cortical circuits. Emerging evidence from human neuroimaging studies further suggests that psychiatric disorders that initially emerge in childhood and adolescence and associated with low blood DHA levels are characterized by frontal circuit deficits compared with healthy developing youth. Based on existing evidence, these associations could have significant implications for informing novel early intervention strategies aimed at reducing the transmission of psychopathology.