Roles of very long chain fatty acids in pathophysiology of FASD

Fetal alcohol spectrum disorders (FASD) are caused by prenatal alcohol exposure (PAE). These children suffer from life-long learning and intellectual disabilities, and other behavioral deficits. Our single cell RNA sequencing of cortical neurons from PAE mouse cortex showed the single cell variability in gene expressions. Among the differentially expressed genes, we found enhanced gene expressions in fatty acid synthesis and modification in a specific neuronal population. Among those genes, Elovl4 is known to be associated with intellectual disabilities. In the endoplasmic reticulum (ER), Elovl4 elongates fatty acids. Under normal conditions, elongated very long chain fatty acids (VLCFAs) in the ER are shuttled to the plasma membranes; however, the fate and function of VLCFAs synthesized by Elovl4 remain elusive. Fatty acids crucially regulate neuronal function and structure, and the disturbed fatty acid synthesis is linked to neurodevelopmental disorders such as autism and ADHD. Therefore, we hypothesized that the increase of Elovl4 in the cerebral cortex is involved in the pathophysiology of the FASD. To examine this hypothesis, we first measured the content of fatty acids in the cerebral cortex after ectopically express Elovl4. Compared to the control brain, Elovl4 overexpression shows the fatty acid profile similar to that of PAE. Second, to define the changes in neuronal membrane dynamics due to Elovl4 overexpression, the fluorescence recovery after photobleaching (FRAP) was performed in the somal and dendritic domains of transfected neurons. Notably, the Elovl4 alters the membrane dynamics only in dendritic domains. Lastly, the single pellet reaching task was assessed in the animals overexpressing Elovl4 in the cortex. Unexpectedly, Elovl4 overexpression causes excessive self-grooming behavior, indicating indirect effects of Elovl4 OE on anxiety or/and repetitive behavior due to the changes in other than cortical region. Altogether, these results suggest a potential contribution of Elovl4 overexpression in FASD-relevant neurobehavior problems, and thus the nutritional or pharmacological intervention focusing on fatty acids may be effective