White matter abnormalities in fetal alcohol spectrum disorders: Focus on axon growth and guidance

Exp Biol Med (Maywood). 2021 Apr;246(7):812-821. doi: 10.1177/1535370220980398. Epub 2021 Jan 10.

Abstract

Fetal Alcohol Spectrum Disorders (FASDs) describe a range of deficits, affecting physical, mental, cognitive, and behavioral function, arising from prenatal alcohol exposure. FASD causes widespread white matter abnormalities, with significant alterations of tracts in the cerebral cortex, cerebellum, and hippocampus. These brain regions present with white-matter volume reductions, particularly at the midline. Neural pathways herein are guided primarily by three guidance cue families: Semaphorin/Neuropilin, Netrin/DCC, and Slit/Robo. These guidance cue/receptor pairs attract and repulse axons and ensure that they reach the proper target to make functional connections. In several cases, these signals cooperate with each other and/or additional molecular partners. Effects of alcohol on guidance cue mechanisms and their associated effectors include inhibition of growth cone response to repellant cues as well as changes in gene expression. Relevant to the corpus callosum, specifically, developmental alcohol exposure alters GABAergic and glutamatergic cell populations and glial cells that serve as guidepost cells for callosal axons. In many cases, deficits seen in FASD mirror aberrancies in guidance cue/receptor signaling. We present evidence for the need for further study on how prenatal alcohol exposure affects the formation of neural connections which may underlie disrupted functional connectivity in FASD.

Keywords: Fetal Alcohol Spectrum Disorder; axon guidance; cerebellum; corpus callosum; hippocampus.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Axons / metabolism*
  • Cerebral Cortex / physiopathology
  • Corpus Callosum / physiopathology
  • Female
  • Fetal Alcohol Spectrum Disorders / physiopathology*
  • Humans
  • Pregnancy
  • Prenatal Exposure Delayed Effects / physiopathology*
  • White Matter / physiopathology*