Submitted by Mark A. TANOUYE on
Epilepsy, a chronic neurological disorder, is characterized by abnormal electrical activity in the central nervous system that manifests as spontaneous, recurrent seizures involving large populations of neurons. Epilepsy is a substantial health problem because of the large number of people affected, the debilitating nature of seizure episodes, and limitations in treatment options. We have developed a Drosophila model based on a collection of neurological mutants: some mutants are sensitive to seizure and resemble human epilepsy syndromes in many aspects; other mutants act to suppress seizures. We have discovered a Drosophila genetic background that is especially sensitized for detecting antiepileptic drugs. This is a special double mutant combination where an epilepsy mutation (sda) in the double mutant contributes seizure-sensitivity. A seizure-suppressor (top1JS) in the double mutant partially suppresses the seizure-sensitivity, so that the combined genotype falls in a phenotypic range whereby antiepileptic drug efficacy can be detected as a simple change in the number of flies undergoing behavioral seizures. That is, the genetic background is sensitized for the detection of antiepileptic drug. Antiepileptic drug compounds are detected because they act synergistically with top1JS to increase seizure-suppression from 20% seizure without drug to 3-8% seizure with drug (valproate, phenytoin, and KBr, three commonly used antiepileptic drugs in humans).
In this project, student researchers will use top1JS; sda double mutant flies to: 1) test the efficacy of known human antiepileptic drugs (gabapentin, carbamazapine, and camptothecin) in suppressing Drosophila seizures; and 2) search a compound library for new antiepileptic drug candidates. Two drug libraries for screening are: the NIH Diversity Set (2,000 compounds) and the Spectrum Collection (2,000 compounds). Twenty flies are fed drug (200ml of drug solution, 10mM drug in 5% sucrose) and tested for behavioral seizures. Results are combined such that n>100 flies for each treatment. Additional tests of drug efficacy will utilize electrophysiological measurements for changes in evoked seizure threshold. In these tests, flies are stimulated with electrodes inserted into the brain. High-frequency stimulus pulses of varying amplitudes are used to evoke seizures. Recording electrodes monitor seizure activity. Epilepsy flies have characteristically low stimulus thresholds for evoked seizures. In flies with seizure-susceptibility suppressed by mutation or drug, seizure threshold voltages are increased.
Our laboratory is seeking an undergraduate research student who can perform experiments in Drosophila genetics and behavior; and then report results to our research team. The student will conduct a research project developing a Drosophila model for human epilepsy that is used in antiepileptic drug testing and identification of novel drug candidates.
We prefer a student with a background in biology, ideally in one of the biology majors (MEB, CRS, PMB). Previous experience working with Drosophila behavioral genetics is preferred including collecting virgin females, performing genetic crosses, identifying and scoring morphological markers, performing behavioral tests for seizure and paralysis.