Article

A Knock-In Model of Human Epilepsy in Drosophila Reveals a Novel Cellular Mechanism Associated with Heat-Induced Seizure

Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697-1280, and Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 10/2012; 32(41):14145-55. DOI: 10.1523/JNEUROSCI.2932-12.2012
Source: PubMed

ABSTRACT Over 40 missense mutations in the human SCN1A sodium channel gene are linked to an epilepsy syndrome termed genetic epilepsy with febrile seizures plus (GEFS+). Inheritance of GEFS+ is dominant, but the underlying cellular mechanisms remain poorly understood. Here we report that knock-in of a GEFS+ SCN1A mutation (K1270T) into the Drosophila sodium channel gene, para, causes a semidominant temperature-induced seizure phenotype. Electrophysiological studies of GABAergic interneurons in the brains of adult GEFS+ flies reveal a novel cellular mechanism underlying heat-induced seizures: the deactivation threshold for persistent sodium currents reversibly shifts to a more negative voltage when the temperature is elevated. This leads to sustained depolarizations in GABAergic neurons and reduced inhibitory activity in the central nervous system. Furthermore, our data indicate a natural temperature-dependent shift in sodium current deactivation (exacerbated by mutation) may contribute to febrile seizures in GEFS+ and perhaps normal individuals.

Download full-text

Full-text

Available from: Diane K O'Dowd, Jun 18, 2015
1 Follower
 · 
143 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human epilepsies encompass a wide variety of clinical, behavioral and electrical manifestations. Correspondingly, studies of this disease in nonhuman animals have brought forward an equally wide array of animal models; that is, species and acute or chronic seizure induction protocols. Epilepsy research has a long history of comparative anatomical and physiological studies on a range of mostly mammalian species. Nonetheless, a relatively limited number of rodent models have emerged as the primary choices for most investigations. In many cases, these animal models are selected on the basis of convenience or tradition, although technical or experimental rationale does, and should, factor into these decisions. More complex mammalian brains and genetic model organisms including zebrafish have been studied less, but offer substantial advantages that are becoming widely recognized.
    Nature Neuroscience 03/2015; 18(3):339-43. DOI:10.1038/nn.3934 · 14.98 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Voltage-gated sodium channels are essential for the initiation and propagation of the action potential in neurons and other excitable cells. Because of their critical roles in electrical signaling, sodium channels are targets of a variety of naturally occurring and synthetic neurotoxins, including several classes of insecticides. This review is intended to provide an update on the molecular biology of insect sodium channels and the molecular mechanism of pyrethroid resistance. Although mammalian and insect sodium channels share fundamental topological and functional properties, most insect species carry only one sodium channel gene, compared to multiple sodium channel genes found in each mammalian species. Recent studies showed that two posttranscriptional mechanisms, alternative splicing and RNA editing, are involved in generating functional diversity of sodium channels in insects. More than 50 sodium channel mutations have been identified to be responsible for or associated with knockdown resistance (kdr) to pyrethroids in various arthropod pests and disease vectors. Elucidation of molecular mechanism of kdr led to the identification of dual receptor sites of pyrethroids on insect sodium channels. Most of the kdr mutations appear to be located within or close to the two receptor sites. The accumulating knowledge of insect sodium channels and their interactions with insecticides provides a foundation for understanding the neurophysiology of sodium channels in vivo and the development of new and safer insecticides for effective control of arthropod pests and human disease vectors.
    Insect biochemistry and molecular biology 04/2014; DOI:10.1016/j.ibmb.2014.03.012 · 3.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hundreds of mutations in the SCN1A sodium channel gene confer a wide spectrum of epileptic disorders, requiring efficient model systems to study cellular mechanisms and identify potential therapeutic targets. We have recently demonstrated that Drosophila knock-in flies carrying a GEFS+ causing SCN1A mutation (K1270T) results in a primarily conditional increase in sodium current activity that contributes to a heat-induced seizure phenotype. To determine whether different SCN1A mutations cause distinct phenotypes in Drosophila as they do in humans, this paper focuses on a knock-in line carrying a mutation that causes a more severe seizure disorder, Dravet Syndrome (DS), in humans. Introduction of the DS SCN1A mutation (S1231R) into the Drosophila sodium channel gene, para, results in flies that exhibit spontaneous and heat-induced seizures with distinct characteristics and lower onset temperature than the GEFS+ flies. Electrophysiological studies of GABAergic interneurons in the brains of adult DS flies reveal, for the first time in an in vivo model system, that a missense DS mutation causes a constitutive and conditional reduction in sodium current activity and repetitive firing. In addition, feeding with the serotonin precursor 5-HTP suppresses heat-induced seizures in DS but not GEFS+ flies. The distinct alterations of sodium currents in DS and GEFS+ GABAergic interneurons demonstrate that both loss- and gain-of-function alterations in sodium currents are capable of causing reduced repetitive firing and seizure phenotypes. The mutation-specific effects of 5-HTP on heat-induced seizures suggest the serotonin pathway as a potential therapeutic target for DS.
    Journal of Neurophysiology 05/2014; 112(4). DOI:10.1152/jn.00135.2014 · 3.04 Impact Factor