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From Genes to Circuits: Genetic Suppression of Epilepsy in Drosophila

  • Author(s): Kroll, Jason
  • Advisor(s): Tanouye, Mark
  • et al.
Abstract

Seizure and epilepsy disorders are debilitating neurological disorders characterized by recurrent, high-frequency and coordinated neural activity. Progress has been made in the last few decades to determine genetic loci and mutations that increase the susceptibility to these various types of neurological disorders. Additionally, much focus has centered on the voltage-gated sodium channel SCN1A, an identified seizure susceptibility gene with over 500 mutations that produce a spectrum of phenotypes in humans. In some types of epilepsy, current anti-epileptic drugs are unsuccessful- and in some cases, even exacerbate the phenotypes, making development of novel anti-epileptic drugs very important. Modeling epilepsies and intractable epilepsies is possible with the model organism Drosophila. In addition for the need of new anti-epileptic drugs, less is known about the extent of how neural circuits are differentially affected by the seizure mutations, which will be important for fully understanding the mechanism of anti-epileptic drugs. In this dissertation, I investigate the circuits involved not only in creating the seizure, but also the circuits that can be utilized to suppress seizures and high-frequency neuronal activity. Using two different approaches of manipulating neural circuits in Drosophila, I identify neurons critical for the seizure sensitivity and for suppression of the seizures. First, through the use of genetic rescue experiments, I determine the sets of neurons that are important for rescuing seizure sensitivity in a seizure-sensitive mutant, finding that primarily excitatory neurons are most effective at suppressing seizures, in contrast to inhibitory neurons, suggesting that the bang-sensitivity in the mutant is due to excess excitatory activity rather than insufficient inhibitory activity. In the next approach, using shibirets1 to restrict synaptic vesicle recycling, I determine the importance of different neurons in the spread or manifestation of the seizure, and what neurons are sufficient for seizure suppression. In different seizure-sensitive mutants, I find that excitatory circuits, and the giant fiber neurons, a pair of neurons involved in the “escape” response and other behaviors, strongly inhibit seizures, making them important neurons within the seizure circuit. Overall, only a portion of the nervous system needs to be targeted by anti-epileptic

drugs or genetic modifications, indicating that the circuits necessary to suppress seizures need not be the same circuits that create them.

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