Oligodendrocyte pathology in fetal alcohol spectrum disorders

Abstract

The pathology of fetal alcohol syndrome and the less severe fetal alcohol spectrum disorders includes brain dysmyelination. Recent studies have shed light on the molecular mechanisms underlying these white matter abnormalities. Rodent models of fetal alcohol syndrome and human studies have shown suppressed oligodendrocyte differentiation and apoptosis of oligodendrocyte precursor cells. Ethanol exposure led to reduced expression of myelin basic protein and delayed myelin basic protein expression in rat and mouse models of fetal alcohol syndrome and in human histopathological specimens. Several studies have reported increased expression of many chemokines in dysmyelinating disorders in central nervous system, including multiple sclerosis and fetal alcohol syndrome. Acute ethanol exposure reduced levels of the neuroprotective insulin-like growth factor-1 in fetal and maternal sheep and in human fetal brain tissues, while ethanol increased the expression of tumor necrosis factor α in mouse and human neurons. White matter lesions have been induced in the developing sheep brain by alcohol exposure in early gestation. Rat fetal alcohol syndrome models have shown reduced axon diameters, with thinner myelin sheaths, as well as reduced numbers of oligodendrocytes, which were also morphologically aberrant oligodendrocytes. Expressions of markers for mature myelination, including myelin basic protein, also were reduced. The accumulating knowledge concerning the mechanisms of ethanol-induced dysmyelination could lead to the development of strategies to prevent dysmyelination in children exposed to ethanol during fetal development. Future studies using fetal oligodendrocyte- and oligodendrocyte precursor cell-derived exosomes isolated from the mother’s blood may identify biomarkers for fetal alcohol syndrome and even implicate epigenetic changes in early development that affect oligodendrocyte precursor cell and oligodendrocyte function in adulthood. By combining various imaging modalities with molecular studies, it may be possible to determine which fetuses are at risk and to intervene therapeutically early in the pregnancy.

Longitudinal effects of prenatal alcohol exposure on visual neurodevelopment over infancy.

“…To explore one potential structural mechanism that could contribute to VEP latencies in development (independent of PAE), we also tested associations in a subsample of infants with an MRI-derived estimate of myelin, the T1w/T2w ratio. PAE has been shown repeatedly to impact myelination (Darbinian & Selzer, 2022; Donald et al, 2015; Ghazi Sherbaf et al, 2019; McLachlan et al, 2019; Newville et al, 2017, 2022; Wozniak & Muetzel, 2011). Moreover, while it is largely accepted that the significant accumulation of myelin in the brain at least partially explains the shortening of VEP latencies across infancy, as far as we are aware, this is the first empirical study to test the relation between cortical myelination and VEP latencies in infancy (though one prior study found decreased subcortical myelination, indexed by diffusion tensor imaging, was linked to longer P1 VEP latencies; Dubois et al, 2008).…”

“…Animal model literature and human literature beginning in childhood have characterized the effects of alcohol exposure on myelination (e.g., Almeida et al, 2020; Darbinian & Selzer, 2022; Milbocker et al, 2022). Human histological studies also provide evidence for the impact of PAE on dysmyelination (Darbinian & Selzer, 2022).…”

“…Animal model literature and human literature beginning in childhood have characterized the effects of alcohol exposure on myelination (e.g., Almeida et al, 2020; Darbinian & Selzer, 2022; Milbocker et al, 2022). Human histological studies also provide evidence for the impact of PAE on dysmyelination (Darbinian & Selzer, 2022). Human neuroimaging studies using MRI found white matter microstructural alterations, including in the occipital lobe, in individuals as young as 5 years of age with PAE and/or FASD (Donald et al, 2015; Ghazi Sherbaf et al, 2019; McLachlan et al, 2019; Wozniak & Muetzel, 2011).…”

“…In summary, sensitive periods are tightly regulated by biological mechanisms including by “brakes” which punctuate these sensitive periods and preserve/protect the learning that has occurred (Gabard-Durnam & McLaughlin, 2020; Hensch & Bilimoria, 2012; Reh et al, 2020; Takesian & Hensch, 2013). Exposure to alcohol prenatally impacts sensitive period regulators such as myelination (Almeida et al, 2020; Darbinian & Selzer, 2022; Donald et al, 2015; Wozniak & Muetzel, 2011), which is a key “brake” on sensitive periods. By disrupting regulators such as myelin, alcohol exposure may shift the timing of postnatal sensitive periods, leading to downstream, potentially disordered consequences on cognition and behavior (e.g., Hensch, 2005; Ivanov, 2021; Makinodan et al, 2012; Marín, 2016; Takesian & Hensch, 2013).…”

Altered markers of brain metabolism and excitability are associated with executive functioning in young children exposed to alcoholin utero

“…Alcohol is a teratogen that can easily cross the placenta, disrupting the fetus’ neurodevelopment at any stage. Disruptions include, but are not limited to, altered neuronal proliferation and migration (Almeida et al, 2020; Veazey et al, 2013), synaptogenesis (Adams et al, 2023; Basavarajappa & Subbanna, 2023), dendritic spine morphology (Cui et al, 2010; Lee et al, 2021), and gliogenesis and myelination (Cantacorps et al, 2017; Darbinian & Selzer, 2022), including phospholipid metabolism (Darbinian et al, 2023; Hwang et al, 2023).…”