Investigation of Seizure-Susceptibility in a Model of Human Epilepsy with Optogenetic Stimulation.

We examined seizure-susceptibility in a model of human epilepsy using optogenetic stimulation of (red-activatable channelrhodopsin). Photostimulation of the seizure-sensitive mutant causes behavioral paralysis that resembles paralysis caused by mechanical stimulation, in many aspects. Electrophysiology shows that photostimulation evokes abnormal seizure-like neuronal firing in followed by a quiescent period resembling synaptic failure and apparently responsible for paralysis.

Seizure Suppression by High Temperature via cAMP Modulation in Drosophila.

Bang-sensitive (BS) Drosophila mutants display characteristic seizure-like activity (SLA) and paralysis after mechanical shock . After high-frequency electrical stimulation (HFS) of the brain, they generate robust seizures at very low threshold voltage. Here we report an important phenomenon, which effectively suppresses SLA in BS mutants.

Mutations of the Calcium Channel Gene cacophony Suppress Seizures in Drosophila.

Bang sensitive (BS) Drosophila mutants display characteristic seizure-like phenotypes resembling, in some aspects, those of human seizure disorders such as epilepsy. The BS mutant parabss1, caused by a gain-of-function mutation of the voltage-gated Na+ channel gene, is extremely seizure-sensitive with phenotypes that have proven difficult to ameliorate by anti-epileptic drug feeding or by seizure-suppressor mutation. It has been presented as a model for intractable human epilepsy.

Disruption of Endocytosis with the Dynamin Mutant shibirets1 Suppresses Seizures in Drosophila.

One challenge in modern medicine is to control epilepsies that do not respond to currently available medications. Since seizures consist of coordinated and high-frequency neural activity, our goal was to disrupt neurotransmission with a synaptic transmission mutant and evaluate its ability to suppress seizures. We found that the mutant shibire, encoding dynamin, suppresses seizure-like activity in multiple seizure-sensitive Drosophila genotypes, one of which resembles human intractable epilepsy in several aspects.

Drosophila sodium channel mutations: Contributions to seizure-susceptibility.

This paper reviews Drosophila voltage-gated Na(+) channel mutations encoded by the para (paralytic) gene and their contributions to seizure disorders in the fly. Numerous mutations cause seizure-sensitivity, for example, para(bss1), with phenotypes that resemble human intractable epilepsy in some aspects. Seizure phenotypes are also seen with human GEFS+ spectrum mutations that have been knocked into the Drosophila para gene, para(GEFS+) and para(DS) alleles.

Modeling glial contributions to seizures and epileptogenesis: cation-chloride cotransporters in Drosophila melanogaster.

Flies carrying a kcc loss-of-function mutation are more seizure-susceptible than wild-type flies. The kcc gene is the highly conserved Drosophila melanogaster ortholog of K+/Cl- cotransporter genes thought to be expressed in all animal cell types. Here, we examined the spatial and temporal requirements for kcc loss-of-function to modify seizure-susceptibility in flies.

Seizure-sensitivity in Drosophila is ameliorated by dorsal vessel injection of the antiepileptic drug valproate.

Drosophila is a powerful model organism that can be used for the development of new drugs directed against human disease. A limitation is the ability to deliver drugs for testing. We report on a novel delivery system for treating Drosophila neurological mutants, direct injection into the circulatory system.

Drosophila as a model for intractable epilepsy: gilgamesh suppresses seizures in para(bss1) heterozygote flies.

Intractable epilepsies, that is, seizure disorders that do not respond to currently available therapies, are difficult, often tragic, neurological disorders. Na(+) channelopathies have been implicated in some intractable epilepsies, including Dravet syndrome (Dravet 1978), but little progress has been forthcoming in therapeutics. Here we examine a Drosophila model for intractable epilepsy, the Na(+) channel gain-of-function mutant para(bss1) that resembles Dravet syndrome in some aspects (parker et al.

Rescue of easily shocked mutant seizure sensitivity in Drosophila adults.

Genetic factors that influence seizure susceptibility can act transiently during the development of neural circuits or might be necessary for the proper functioning of existing circuits. We provide evidence that the Drosophila seizure-sensitive mutant easily shocked (eas) represents a neurological disorder in which abnormal functioning of existing neural circuits leads to seizure sensitivity. The eas(+) gene encodes for the protein Ethanolamine Kinase, involved in phospholipid biosynthesis.

Seizure and epilepsy: studies of seizure disorders in Drosophila.

Despite the frequency of seizure disorders in the human population, the genetic and physiological basis for these defects has been difficult to resolve. Although many genetic contributions to seizure susceptibility have been identified, these involve disparate biological processes, many of which are not neural specific. The large number and heterogeneous nature of the genes involved makes it difficult to understand the complex factors underlying the etiology of seizure disorders.

Drosophila as a model for epilepsy: bss is a gain-of-function mutation in the para sodium channel gene that leads to seizures.

We report the identification of bang senseless (bss), a Drosophila melanogaster mutant exhibiting seizure-like behaviors, as an allele of the paralytic (para) voltage-gated Na(+) (Na(V)) channel gene. Mutants are more prone to seizure episodes than normal flies because of a lowered seizure threshold. The bss phenotypes are due to a missense mutation in a segment previously implicated in inactivation, termed the "paddle motif" of the Na(V) fourth homology domain.

Seizure sensitivity is ameliorated by targeted expression of K+-Cl- cotransporter function in the mushroom body of the Drosophila brain.

The kcc(DHS1) allele of kazachoc (kcc) was identified as a seizure-enhancer mutation exacerbating the bang-sensitive (BS) paralytic behavioral phenotypes of several seizure-sensitive Drosophila mutants. On their own, young kcc(DHS1) flies also display seizure-like behavior and demonstrate a reduced threshold for seizures induced by electroconvulsive shock. The product of kcc shows substantial homology to KCC2, the mammalian neuronal K(+)-Cl(-) cotransporter.

Neurocircuit assays for seizures in epilepsy mutants of Drosophila.

Drosophila melanogaster is a useful tool for studying seizure like activity. A variety of mutants in which seizures can be induced through either physical shock or electrical stimulation is available for study of various aspects of seizure activity and behavior. All flies, including wild-type, will undergo seizure-like activity if stimulated at a high enough voltage.

From bench to drug: human seizure modeling using Drosophila.

Studies of human seizure disorders have revealed that susceptibility to seizures is greatly influenced by genetic factors. In addition to causing epilepsy, genetic factors can suppress seizures and epileptogenesis. Examination of seizure-suppressor genes is challenging in humans.

Mutations in the K+/Cl- cotransporter gene kazachoc (kcc) increase seizure susceptibility in Drosophila.

During a critical period in the developing mammalian brain, there is a major switch in the nature of GABAergic transmission from depolarizing and excitatory, the pattern of the neonatal brain, to hyperpolarizing and inhibitory, the pattern of the mature brain. This switch is believed to play a major role in determining neuronal connectivity via activity-dependent mechanisms. The GABAergic developmental switch may also be particularly vulnerable to dysfunction leading to seizure disorders.

Making an escape: development and function of the Drosophila giant fibre system.

Flies escape danger by jumping into the air and flying away. The giant fibre system (GFS) is the neural circuit that mediates this simple behavioural response to visual stimuli. The sensory signal is received by the giant fibre and relayed to the leg and wing muscle motorneurons.

Seizure suppression by shakB2, a gap junction mutation in Drosophila.

Gap junction proteins mediate electrical synaptic transmission. In Drosophila, flies carrying null mutations in the shakB locus, such as shakB2, have behavioral and electrophysiological defects in the giant fiber (GF) system neurocircuit consistent with a loss of transmission at electrical synapses. The shakB2 mutation also affects seizure susceptibility.

The mei-P26 gene encodes a RING finger B-box coiled-coil-NHL protein that regulates seizure susceptibility in Drosophilia.

Seizure-suppressor mutations provide unique insight into the genes and mechanisms involved in regulating nervous system excitability. Drosophila bang-sensitive (BS) mutants present a useful tool for identifying seizure suppressors since they are a well-characterized epilepsy model. Here we describe the isolation and characterization of a new Drosophila seizure-suppressor mutant that results from disruption of the meiotic gene mei-P26, which belongs to the RBCC-NHL family of proteins.

Drosophila couch potato mutants exhibit complex neurological abnormalities including epilepsy phenotypes.

RNA-binding proteins play critical roles in regulation of gene expression, and impairment can have severe phenotypic consequences on nervous system function. We report here the discovery of several complex neurological phenotypes associated with mutations of couch potato (cpo), which encodes a Drosophila RNA-binding protein. We show that mutation of cpo leads to bang-sensitive paralysis, seizure susceptibility, and synaptic transmission defects.

Seizure suppression by gain-of-function escargot mutations.

Suppressor mutations provide potentially powerful tools for examining mechanisms underlying neurological disorders and identifying novel targets for pharmacological intervention. Here we describe mutations that suppress seizures in a Drosophila model of human epilepsy. A screen utilizing the Drosophila easily shocked (eas) "epilepsy" mutant identified dominant suppressors of seizure sensitivity.

Potassium bromide, an anticonvulsant, is effective at alleviating seizures in the Drosophila bang-sensitive mutant bang senseless.

Human seizure disorders are a major health concern due to the large number of affected individuals, the potentially devastating consequences of untreated seizure occurrences, and the lack of an effective treatment for all patients. Although anticonvulsants have proven very helpful in treating seizures and remain the best option available for treatment, not all afflicted individuals respond to medication and many only do so in unique drug combinations or at the cost of adverse side-effects. Therefore, new and more effective anticonvulsants are continually sought after to combat this illness.

Genome-wide analysis of the odorant-binding protein gene family in Drosophila melanogaster.

Olfaction is of considerable importance to many insects in behaviors critical for survival and reproduction, including location of food sources, selection of mates, recognition of colony con-specifics, and determination of oviposition sites. An ubiquitous, but poorly understood, component of the insect's olfactory system is a group of odorant-binding proteins (OBPs) that are present at high concentrations in the aqueous lymph surrounding the dendrites of olfactory receptor neurons. OBPs are believed to shuttle odorants from the environment to the underlying odorant receptors, for which they could potentially serve as odorant presenters.