021 - The effect of synaptamide signaling on neurodevelopmental outcomes in a mouse model

Publication Number: 21.6640

Joel A. Toro, Uniformed Services University of the Health Sciences F. Edward Hebert School of Medicine, Gaithersburg, MD, United States; Hee-Yong Kim, National Institutes of Health, Rockville, MD, United States

Background: Docosahexaenoic acid (DHA) is an omega-3 fatty acid essential for brain development and has a role in cognitive and memory function. N-docosahexaenoylethanolamine, also known as synaptamide, is an endogenous metabolite of DHA that potently increases neurogenesis, synaptogenesis and glutamatergic synaptic activity during development via binding to the receptor GPR110. It has been shown that the levels of synaptamide and DHA highly correlate. Babies born prematurely have a deficit of DHA, which may compromise synaptamide-induced brain development. In one study, DHA supplementation in preterm neonates improved intelligence scores at 5 years of age, but other developmental outcomes have not been examined.

Objective: Hypothesis: GPR110 KO mice lacking synaptamide-induced neurodevelopmental signaling will have worse neurodevelopmental outcomes at 2-4 months when compared to wildtype (WT) mice

Design/Methods: GPR110 KO mice were generated by the UC Davis Knock Out Mouse Project (KOMP). WT and GPR110KO mice continued to be generated by in-house mating of GPR110+/-. At 2-4 months of life, WT and KO mice underwent neurodevelopmental studies to assess for anxiety-related behaviors using marble burying test (MBT) and elevated plus maze (EPM), social withdrawal using the nestlet shredding test (NST) and motor deficits using rotarod testing. Data was analyzed using t-Test: Two-Sample Assuming Equal Variances.

Results: GPR110 KO mice demonstrated increased time within closed arms in the EPM (p=0.002) and increased the number of marbles buried within 30 minutes in the MBT (p=0.001). There was no significant difference between WT and KO mice in the amount of nestlet shredded within 30 minutes in the NST (p=0.25), nor in time remaining on the rotarod p=0.14

Conclusion(s): This study is the first to evaluate the impact of synaptamide-induced signaling, a potently bioactive metabolite of DHA, in neurodevelopmental testing apart from intelligence. Differences between WT and GPR110 KO mice during EPM and MBT testing indicate that deficits in synaptamide signaling increase anxiety levels in this mouse model. Lack of significant differences in the NST test and rotarod test indicate probable lack of impact of synaptamide on social and motor function in this mouse model. These results can help focus further evaluation into neurodevelopmental impacts of DHA that determines the synaptamide levels, and thus synaptamide-induced GPR110 signaling. Further studies about other neurodevelopmental outcomes will provide added insights into the impact of DHA deficiencies, a risk in preterm neonates, and direct future interventions.