Effects of memantine on mania-like phenotypes exhibited by Drosophila Shaker mutants

Introduction: Increased glutamate levels and electrolytic fluctuations have beenobserved in acutely manic patients. Despite some efficacy of the non-competitiveNMDA receptor antagonist memantine (Mem), such as antidepressant-likeand mood-stabilizerdrugs in clinical studies, its specific mechanisms of action are still uncertain.The present study aims to better characterize the Drosophila melanogaster fly Shakermutants (SH), as a translational model of manic episodes within bipolar disorder inhumans, and to investigate the potential anti-manicproperties of Mem.Methods and Results: Our findings showed typical behavioral abnormalities in SH,which mirrored with the overexpression of NMDAR-NR1protein subunit, matchedwell to glutamate up-regulation.Such molecular features were associated to a significantreduction of SH brain volume in comparison to Wild Type strain flies (WT). Herewe report on the ability of Mem treatment to ameliorate behavioral aberrations ofSH (similar to that of Lithium), and its ability to reduce NMDAR-NR1over-expression.Conclusions: Our results show the involvement of the glutamatergic system in the SH,given the interaction between the Shaker channel and the NMDA receptor, suggestingthis model as a promising tool for studying the neurobiology of bipolar disorders.Moreover, our results show Mem as a potential disease-modifyingtherapy, providinginsight on new mechanisms of action.