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Overexpressions of Fatty Acid-Related Genes During Neurodevelopment in a FASD Model Open Access

Fetal Alcohol Spectrum Disorders (FASD), caused by prenatal alcohol exposure (PAE), is characterized by congenital central nervous system dysfunction resulting in impaired learning and motor skill deficits. FASD affects 2-5% of children in the U.S., with similar or higher rates reported worldwide. Subsequent single-cell RNA-sequencing in cortex of PAE mice showed variable gene expressions of individual neurons that persisted throughout life. Markedly, high expressions of fatty acid elongase 4 (ELOVL4) and fatty acid synthase (FASN), genes involved in fatty acid biosynthesis, were observed in a specific neuronal population in the PAE mouse cortex. FASN encodes a multi-enzyme protein involved in synthesis of palmitate into long-chain saturated fatty acids, and ELOVL4 encodes a membrane-bound protein involved in elongation of very long chain saturated and polyunsaturated fatty acids in the brain. Fatty acids are essential for regulating neuronal structure and function, and interferences in fatty acid metabolism are associated with neurodevelopmental disorders like autism and ADHD. Changes of fatty acid contents suggestively serve as peripheral biomarkers of FASD. However, functions of fatty acids synthesized by ELOVL4 and FASN remain unknown, and pathological mechanisms due to disturbed fatty acid contents in the brain are elusive. Our working hypothesis is that increase of these fatty acid-related gene expressions in the cerebral cortex is involved in the pathophysiology of FASD. To examine this hypothesis, we first tested if the increases of these genes occur at the protein level by performing immunohistochemistry. We further tested the pattern of increases; which types of neuronal cells and cortical regions show the increase, and which subcellular compartments show the increase of the expressions. In this presentation, based on the staining results, we will discuss how the expressions of fatty acid-related genes are altered due to the effects of PAE.

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