Pharmacological rescue of motor circuit dysfunction in aDrosophilamodel of paroxysmal dyskinesia

Abstract

BackgroundParoxysmal dyskinesias (PxDs) are characterised by bouts of involuntary dystonic and choreiform movements. The patho-mechanisms underlying these debilitating disorders remain poorly understood, and drug treatments are often limited. We recently generated aDrosophilamodel of a PxD-linked mutation causing BK potassium channel gain- of-function (BK GOF), and showed that BK GOF perturbs movement inDrosophilaby disrupting neurodevelopment. However, whether locomotor capacity in BK GOF flies can be pharmacologically restored following neurodevelopmental insults has remained unclear.ObjectiveTo identify pharmacological suppressors of motor defects caused by BK GOF.MethodsUsing adult BK GOF flies, we performed an unbiased, in vivo, locomotion-based screen of 370 FDA-approved drugs. To test the impact of positive hits from this screen on motor circuit activity, we used optical imaging to record the intrinsic rhythmic activity ofDrosophilalarval motor circuits driving peristalsis and turning behaviors.ResultsWe found that inhibitors of acetylcholinesterase – a protein that degrades acetylcholine in cholinergic synapses – partially rescued movement defects caused by BK GOF. Inhibition of acetylcholinesterase also partially restored intrinsic activity of motor circuits controlling forward movement and turning in BK GOF larvae.ConclusionsOur findings indicate that elevating cholinergic tone can reverse motor circuit dysfunction in an animal model of PxD caused by BK GOF. Furthermore, our study provides proof-of-principle thatDrosophilacan be utilised for screens to uncover putative drug treatments for involuntary movement disorders.