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

Sun, Lei; Gilligan, Jeff; Staber, Cynthia; Schutte, Ryan J.; Nguyen, Vivian My; O’Dowd, Diane K.; Reenan, Robert A.

doi:10.1523/jneurosci.2932-12.2012

Cited by 79 publications

(138 citation statements)

References 43 publications

(56 reference statements)

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“…Heat-induced seizure assay was performed as described in Sun et al (2012) using 5-d-old flies. Individual flies were isolated in a glass vial (15 × 45 mm) and acclimated for 15–30 min.…”

Section: Methodsmentioning

confidence: 99%

Lithium-Responsive Seizure-Like Hyperexcitability Is Caused by a Mutation in theDrosophilaVoltage-Gated Sodium Channel Geneparalytic

Kaas

Kasuya

Lansdon

et al. 2016

eNeuro

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Shudderer (Shu) is an X-linked dominant mutation in Drosophila melanogaster identified more than 40 years ago. A previous study showed that Shu caused spontaneous tremors and defects in reactive climbing behavior, and that these phenotypes were significantly suppressed when mutants were fed food containing lithium, a mood stabilizer used in the treatment of bipolar disorder (Williamson, 1982). This unique observation suggested that the Shu mutation affects genes involved in lithium-responsive neurobiological processes. In the present study, we identified Shu as a novel mutant allele of the voltage-gated sodium (Nav) channel gene paralytic (para). Given that hypomorphic para alleles and RNA interference–mediated para knockdown reduced the severity of Shu phenotypes, Shu was classified as a para hypermorphic allele. We also demonstrated that lithium could improve the behavioral abnormalities displayed by other Nav mutants, including a fly model of the human generalized epilepsy with febrile seizures plus. Our electrophysiological analysis of Shu showed that lithium treatment did not acutely suppress Nav channel activity, indicating that the rescue effect of lithium resulted from chronic physiological adjustments to this drug. Microarray analysis revealed that lithium significantly alters the expression of various genes in Shu, including those involved in innate immune responses, amino acid metabolism, and oxidation-reduction processes, raising the interesting possibility that lithium-induced modulation of these biological pathways may contribute to such adjustments. Overall, our findings demonstrate that Nav channel mutants in Drosophila are valuable genetic tools for elucidating the effects of lithium on the nervous system in the context of neurophysiology and behavior.

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“…Heat-induced seizure assay was performed as described in Sun et al (2012) using 5-d-old flies. Individual flies were isolated in a glass vial (15 × 45 mm) and acclimated for 15–30 min.…”

Section: Methodsmentioning

confidence: 99%

Lithium-Responsive Seizure-Like Hyperexcitability Is Caused by a Mutation in theDrosophilaVoltage-Gated Sodium Channel Geneparalytic

Kaas

Kasuya

Lansdon

et al. 2016

eNeuro

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“…Even small changes in sodium channel expression and/or function could be biologically relevant, as underscored by sodium channel mutations that cause various behavioral defects in D. melanogaster (Garber et al, 2012; Lilly et al, 1994; Lindsay et al, 2008; Parker et al, 2011; Sun et al, 2012; Wang et al, 1997). In addition, identification of alternative splicing and RNA-editing variants that have unique gating properties provided a valuable resource to gain insights into specific amino acid sequences/residues that are critical for channel function and interactions of sodium channels with insecticides and other toxins (Du et al, 2006; Du et al, 2009c; Du et al, 2010; Silver et al, 2014; Song et al, 2011; Song et al, 2006; Tan et al, 2002a).…”

Section: Insects Achieve Functional Diversity Of Sodium Channels Vmentioning

confidence: 99%

Molecular biology of insect sodium channels and pyrethroid resistance

Dong

Rinkevich

et al. 2014

Insect Biochemistry and Molecular Biology

408

561

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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.

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“…For example, in mice and humans, missense mutations of the Cacna1a calcium channel have been linked to absence seizures, while in Drosophila, mutations in the homologous cac TS2 channel result in heat-activated seizures but are also a suppressor of bang-sensitive mutants (Zamponi et al 2009). Additionally, there are different para alleles in Drosophila that can cause either bang sensitivity, seizure suppression, heat-activated seizure sensitivity, cold sensitivity, or temperature-sensitive paralysis, all extremes of either hyperor hypoactivity of the sodium channel (Lindsay et al 2008;Parker et al 2011b;Sun et al 2012;Schutte et al 2014).…”

Section: Dual Roles Of Dynamin and Other Epilepsy-related Genes In Nementioning

confidence: 99%

Disruption of Endocytosis with the Dynamin Mutantshibirets1Suppresses Seizures inDrosophila

et al. 2015

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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. Because of the requirement of dynamin in endocytosis, increased temperature in the shi ts1 mutant causes impairment of synaptic vesicle recycling and is associated with suppression of the seizure-like activity. Additionally, we identified the giant fiber neuron as critical in the seizure circuit and sufficient to suppress seizures. Overall, our results implicate mutant dynamin as an effective seizure suppressor, suggesting that targeting or limiting the availability of synaptic vesicles could be an effective and general method of controlling epilepsy disorders.

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

Cited by 79 publications

References 43 publications

Lithium-Responsive Seizure-Like Hyperexcitability Is Caused by a Mutation in theDrosophilaVoltage-Gated Sodium Channel Geneparalytic

Lithium-Responsive Seizure-Like Hyperexcitability Is Caused by a Mutation in theDrosophilaVoltage-Gated Sodium Channel Geneparalytic

Molecular biology of insect sodium channels and pyrethroid resistance

Disruption of Endocytosis with the Dynamin Mutantshibirets1Suppresses Seizures inDrosophila

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