Slamdance: seizing a fly model for epilepsy.

BRAIN SEIZURES, AS IN EPILEPSY, are characterized by massively synchronous firing of neurons. Given the extraordinary complexity of the human brain, it is surprising that epilepsy is not a more common complaint. Episodic brain seizures currently affect 1% of the human population, and causes for the syndrome range from hereditary effects to brain injuries and infectious diseases (Berg 2011). To better understand seizures and how they may be prevented requires access to animal models where behavior and neurophysiology can be easily studied together, ideally in mutant strains relevant to human epilepsies. A recent study by Marley and Baines (2011) presents just such a model using the fruit fly Drosophila melanogaster, and in the process, this study provides evidence for correction mechanisms in two different neurons in response to seizure-inducing mutations or anti-epileptic drug (AED) therapy. Drosophila has been well established as a model to study epilepsy, although the fly has been until recently less revealing about neural currents underpinning epileptic phenotypes. In early behavioral screens of Drosophila, Seymour Benzer (1971) noted that a number of mutant strains were transiently knocked out following mechanical stimulation, and these mutants were termed “bang-sensitive (b-s)”. Genetic identification of several of these mutations revealed defective ion channels and synaptic machinery (George 2005; Song and Tanouye 2008) that likely induce seizures in the fly. Limited access to brain electrophysiology in the fly has prevented a better understanding of how these mutations lead to epileptiform activity (Glasscock and Tanouye 2005; Pavlidis et al. 1994). However, Marley and Baines (2011) provide a fresh insight by recording from larval neurons in the brains of slamdance (sda) b-s mutants. Voltage-gated sodium currents are compromised in sda mutants due to a defective aminopeptidase pathway (Zhang et al. 2002), producing an epileptic phenotype in fly larvae following electric shock. Mean behavioral recovery times following seizure episodes in sda flies are over five times longer than for wild-type animals, mimicking similar effects in adults following mechanical shock. Recordings from two motor neurons (termed aCC and RP2) reveal increased amplitude and duration of spontaneous rhythmic synaptic currents in the mutants, and this appears to be associated with altered sodium currents. Whole cell voltage clamp recordings from aCC and RP2 neuronal cell bodies revealed two components of membrane sodium currents, the transient (INat) and persistent (INap) components, produced by different conductance states of the same DmNav channel (Lin et al. 2009) (Fig. 1A). However, only the smaller persistent current was increased in sda mutants, whereas the transient current remained unchanged (Fig. 1A). INap has previously been shown to be relevant in human epilepsy, and is a potential target for drug therapies (George 2005; Segal and Douglas 1997). Hence, an effect of sda on this current component already suggests that this mutant is a potentially suitable fly model for epilepsy. Since INap has been a target for drug intervention in human epilepsy therapy, it was hypothesized that AEDs might correct seizure-like symptoms in sda mutants. Indeed, feeding the mutants phenytoin (an AED) was found to dramatically reduce mean recovery times to wild-type levels. This behavioral effect of the drug was associated with reduced INap currents in the mutant while INat remained unchanged. As further evidence linking the persistent sodium current with seizure-like effects in fly larvae, another drug (rATXII) was used to potentiate INap in wild-type flies. Above an INap/INat ratio of 35%, increasing INap was found to promote seizure-like behavior in larvae, whereas below this threshold larvae displayed wild-type responses to electric shock. Together with the observations in sda mutants (Fig. 1B), these results firmly implicate the persistent sodium current (INap) as primarily responsible for epileptic behavior in this fly model. Although effective, anti-epileptic drugs can cause developmental defects. It has been reported that some children born to epileptic mothers who were administered AEDs throughout their pregnancies had impaired cognitive functions (Hanson et al. 1976; Holmes 2009), and genetic predisposition to seizures was still evident in these children as well (Hanson et al. 1976; Holmes 2009). Marley and Baines (2011) conducted an experiment in Drosophila to determine the effects on progeny of feeding AEDs to gravid seizure-prone sda females. Gravid sda females were fed phenytoin, which decreases INap and prevents seizures in those animals, as discussed above. The feeding regime allowed subthreshold amounts of phenytoin to be transferred to the eggs. However, the eggs laid by these mutant females, and the larvae that subsequently hatched, were not exposed to the drug. Instead of observing defects in the offspring (termed sda-treated animals), the authors observed significantly reduced seizure susceptibility in the next generation, and this was associated with a lower INap/INat ratio. Similar drug treatments in rodents have indicated some positive outcomes on offspring, but not to the extent observed here (Blumenfeld et al. 2008). Therefore, why such a clear-cut result in Drosophila? Marley and Baines (2011) hypothesize that imbalances in excitation and inhibition in early stages of neural development could lead to seizures. Early pharmaceutical intervention by administering phenytoin may correct for this imbalance or prevent the imbalance from occurring. The simpler nervous system in Drosophila may be less susceptible Address for reprint requests and other correspondence: S. Karunanithi, School of Biomedical Sciences, Charles Sturt University, Bathurst, New South Wales, Australia (e-mail: [email protected]; B. van Swinderen, e-mail: [email protected]). J Neurophysiol 106: 15–17, 2011. doi:10.1152/jn.00382.2011.