Acute oligodendrocyte loss with persistent white matter injury in a third trimester equivalent mouse model of fetal alcohol spectrum disorder

Abstract

Alcohol exposure during central nervous system (CNS) development can lead to fetal alcohol spectrum disorder (FASD). Human imaging studies have revealed significant white matter (WM) abnormalities linked to cognitive impairment in children with FASD, however the underlying mechanisms remain unknown. Here, we evaluated both the acute and long-term impacts of alcohol exposure on oligodendrocyte number and WM integrity in a third trimester-equivalent mouse model of FASD, in which mouse pups were exposed to alcohol during the first two weeks of postnatal development. Our results demonstrate a 58% decrease in the number of mature oligodendrocytes (OLs) and a 75% decrease in the number of proliferating oligodendrocyte progenitor cells (OPCs) within the corpus callosum of alcohol-exposed mice at postnatal day 16 (P16). Interestingly, neither mature OLs nor OPCs derived from the postnatal subventricular zone (SVZ) were numerically affected by alcohol exposure, indicating heterogeneity in susceptibility based on OL ontogenetic origin. Although mature OL and proliferating OPC numbers recovered by postnatal day 50 (P50), abnormalities in myelin protein expression and microstructure within the corpus callosum of alcohol-exposed subjects persisted, as assessed by western immunoblotting of myelin basic protein (MBP; decreased expression) and MRI diffusion tensor imaging (DTI; decreased fractional anisotropy). These results indicate that third trimester-equivalent alcohol exposure leads to an acute, albeit recoverable, decrease in OL lineage cell numbers, accompanied by enduring WM injury. Additionally, our finding of heterogeneity in alcohol susceptibility based on the developmental origin of OLs may have therapeutic implications in FASD and other disorders of WM development.

Ethanol Exposure Increases miR‐140 in Extracellular Vesicles: Implications for Fetal Neural Stem Cell Proliferation and Maturation

“…Consequently, the loss of neuronal lineage following miR‐140‐3p overexpression may indirectly result in aberrant astrocytic maturation and contribute to aberrant astrocyte function that has been associated with prenatal alcohol exposure (Wilhelm et al., ). The loss of oligodendroglial markers following miR‐140‐3p overexpression is also consistent with the appearance of white matter abnormalities in FASD (Norman et al., ) and loss of oligodendrocytes (Newville et al., ) in the models of PAE. Thus, the dysregulated miRNA content of neural progenitor EVs following EtOH exposure may underlie some of the aberrant brain maturation associated with FASD.…”

Resistance of Postnatal Hippocampal Neurogenesis to Alcohol Toxicity in a Third Trimester‐Equivalent Mouse Model of Gestational Alcohol Exposure

“…007909; Madisen et al., ). Tamoxifen administration results in Cre‐mediated recombination and tdTom reporter expression within nestin + hippocampal progenitors and downstream progeny (Cunningham et al., ; Lagace et al., ; Li et al., ; Newville et al., ). All animal procedures were approved by the University of New Mexico Health Sciences Center Institutional Animal Care and Use Committee guidelines per the NIH Animal Welfare Regulations and Public Health Service Policy on Human Care and Use of Laboratory Animals.…”

“…Cages containing mothers and pups were placed into vapor inhalation chambers from PND 3 through PND 15. Either EtOH vapor or air (control) was pumped into the chamber for 4 h/d between 10:00 and 14:00 hour, as previously described (Newville et al., ). EtOH vapor levels were measured at the end of each 4‐hour exposure period using a breathalyzer (Intoximeters, St Louis, MO, 12‐0050‐00).…”

“…In the present study, we asked whether exposure to EtOH vapor during the period of peak dentate neurogenesis in the early postnatal period (~human third trimester‐equivalent for brain development) impairs the production and/or long‐term survival of dDGCs, and/or the production of aDGCs under conditions of SH or EE. We utilized vapor chambers to deliver EtOH to mouse pups during the first 2 weeks of postnatal development at a dose known to result in acute oligodendrocyte loss and persistent white matter injury (Newville et al., ). We utilized a well‐characterized Cre‐loxP genetic labeling approach in NestinCreER T2 :tdTomato bitransgenic mice to identify newborn DGCs.…”

Genetic inactivation of synaptosomal‐associated protein 25 (SNAP‐25) in adult hippocampal neural progenitors impairs pattern discrimination learning but not survival or structural maturation of newborn dentate granule cells

“…Mice were single housed for 2 days post-surgery and placed back into enrichment cages for 8 weeks prior to sacrifice for histological assessment of dendritic and axonal morphology as described below. Immunoresearch, West Grove, PA), using a previously published protocol (Newville, Valenzuela, Li, Jantzie, & Cunningham, 2017). Sections were counterstained with 4 0 ,6-diamidino-2-phenylindole (DAPI) nuclear dye, mounted onto glass slides and coverslipped with Fluoromount G (ThermoFisher Scientific, Waltham, MA).…”