CREATING A DROSOPHILA MODEL OF DYSTONIA
Describing evoked hyperkinetic and dyskinetic movements
Dystonia is the 3rd most common movement disorder, typified by twisting and/or posturing movements. Human dystonia can be precipitated by sensory stimuli including heat, mechanosensory sensation, or passive or volitional movement. Dystonia-like movements manifest in flies with mutations in orthologs of dystonia genes as hypokinetic or hyperkinetic repetitive movements evoked by mechanical and/or thermal stimulation. This is thought to be due to increased heat increasing synaptic transmission and excitatory neuronal drive.
MECHANICALLY EVOKED DYSKINESIAS
Drosophila subjected to mechanical stimulation (vortexing for 10 seconds) display increased motor activity with uncoordinated leg and wing movements. In extreme cases, this can result in rigid limbs (hypertonia) and temporary paralysis. The sensitivity can be measured by the amount of time needed to stop hyperkinetic/dyskinetic movements, stand, and resume normal volitional movements. While normal flies recover quite quickly, several genetic models of dystonia have increased time to recover with more frequent paralysis. We identified acetylcholine neurons as important for suppressing hyperkinetic and dyskinetic movements after mechanical stimulation for facilitating recovery.
HEAT EVOKED DYSKINESIAS
Drosophila subjected to increased temperatures of 37˚C display increased motor activity with increased jumps and flights. While normal flies are quite skilled at moving their body in 3-D space to coordinate successful landings on their feet, our model of dystonia had dyskinetic and uncoordinated landings. Additionally, we observed hyperkinetic movements as wing fluttering in the absence of flight only in this dystonia model. We identified neurons expressing D2-dopamine receptors as important for suppressing uncoordinated dyskinetic movements and hyperkinetic wing movements during heat exposure.
MOLECULAR MECHANISMS OF DYSTONIA
The molecular and cellular mechanisms connecting genetic and environmental insults to altered brain circuit connectivity and dystonia are not known. A protein translation factor, eIF2α, is phosphorylated (eIF2α-P) to decrease global protein translation and upregulate plasticity and stress-response genes. In dystonia models eIF2α-P was abnormally elevated, but whether eIF2α-P can directly alter motor circuit properties was unknown. We find altering eIF2α-P produces abnormal posturing and disordered movements in flies, recapitulating the dystonia-like dyskinetic movements previously observed in the DYT1 fly model. We are also using the eIF2α-P Drosophila model to determine how increases/decreases of eIF2α-P can affect neuron function and synaptic connectivity.