Endocannabinoids Protect Against Seizures In Drosophila Melanogaster

Cannabinoids are generally anticonvulsive molecules, but their mechanism of action remains controversial as they can have effects independent of canonical cannabinoid receptors. The goal of my thesis, therefore, was to identify how cannabinoids protect against seizures through these non-canonical, cannabinoid signaling pathways. To achieve this goal I used Drosophila melanogaster, an animal that lacks canonical cannabinoid receptors, but possess other components of the endocannabinoid system. I found that feeding the endocannabinoid anandamide is protective in multiple fly seizure models and that the protective effect of anandamide is mediated by its metabolite, arachidonic acid, acting at the TRP channel Water witch. The endocannabinoid 2-arachidonoylglycerol is also protective in multiple fly seizure models, including a fly model of human Generalized Epilepsy with Febrile Seizures Plus. This effect is likely mediated by positive allosteric modulation of GABAARs. Through the novel use of fruit flies to understand cannabinoid signaling, I demonstrate that endocannabinoids are anticonvulsant in an animal that lacks canonical cannabinoid receptors and identify two mechanisms that mediate these anticonvulsant effects. It is my hope that findings from this study translate to mammals and are used to inform the development of new antiepileptic drugs.