Slamdance: seizing a fly model for epilepsy

Abstract

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 ϳ1% 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 (I Nat ) and persistent (I Nap ) components, produced by different conductance states of the same DmNa v 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). I Nap 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 th...