Roles of Very Long Chain Fatty Acids in Neurobehavior Deficits in FASD

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PROJECT SUMMARY This application focuses on investigating the underlying mechanism of neurobehavioral problems in Fetal Alcohol Spectrum Disorders (FASD) using a mouse model. Alcohol damages developing brain by affecting multifaceted process, thereby leading to lifelong cognitive and neurobehavioral deficits. Previous studies showed the disturbances in fatty acid contents in FASD brains, however, the contribution of the disruption to the neurobehavioral problems still remain elusive. Our preliminary study identified abnormal (excess) expression of a fatty acid related gene, Elongation of Very Long Chain Fatty Acids 4 (Elovl4), in pyramidal neurons in motor cortex in young adult mice long after prenatal alcohol exposure (PAE). Given that fatty acids play imperative roles in brain development and neuronal function, I hypothesize that disrupted fatty acid biogenesis due to excess Elovl4 contributes to impairment of motor skill learning in PAE mice. To test this hypothesis, I will profile fatty acid species in phospholipids of cellular membrane in PAE motor cortex. Similarly, the effects of Elovl4 overexpression on fatty acid profile will be determined and compared with those of PAE, so that we can examine the contribution of Elovl4 to disruption of fatty acids in PAE (Aim 1). In aim 2, to define the effects on neuronal functions at cellular level, membrane dynamics and synaptic plasticity will be examined in the neurons with Elovl4 overexpression and the PAE neurons. Lastly, to test whether disruption of Elovl4 gene is responsible for motor skill learning deficits in PAE mice, I will test whether knocking down of Elovl4 ameliorates the impaired motor skill learning (Aim 3). The results of the proposed study may reveal hitherto unknown pathological mechanism of learning deficits due to disruption of fatty acid biogenesis in FASD, thereby leading to potential interventions.