Zebrafish as a model for studying genetic aspects of epilepsy

Hortopan, G.A.; Dinday, Matthew T.; Baraban, Scott C.

doi:10.1242/dmm.002139

Cited by 147 publications

(101 citation statements)

References 49 publications

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“…Touch‐evoked escape responses (TEER) were used to quantify swimming velocity, distance, duration, as well as the trajectory tortuosity. Similar to previous studies reporting genetic and pharmacological models of epilepsy in zebrafish,19 aberrant locomotion was characterized by tortuous, cork‐screw swimming bouts (Fig. 3A).…”

Section: Resultssupporting

confidence: 84%

“…Reports of genetically and chemically induced zebrafish models of epilepsy (reviewed in 19, 24, 37, 38), have established a number of behavioral paradigms that are used as metrics in this field. These measures are generally obtained at larval stages 3–7 dpf upon evoked or spontaneous swimming episodes 20, 21, 28, 39.…”

Section: Discussionmentioning

confidence: 99%

“…Zebrafish in particular has recently emerged as a prominent vertebrate genetic model for epilepsy‐related mutations18, 19 due to the relative ease of genetic manipulation, rapid development, and small size amenable to high‐throughput screening methods. There is only one orthologue of DEPDC5 in zebrafish; the level of identity of the zebrafish depdc5 and human DEPDC5 is 75%, with members of the mTOR pathway being equally well conserved (Table S1).…”

Section: Introductionmentioning

confidence: 99%

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Depdc5 knockdown causes mTOR‐dependent motor hyperactivity in zebrafish

Calbiac

Dabacan²,

Marsan

et al. 2018

Ann Clin Transl Neurol

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Objective DEPDC5 was identified as a major genetic cause of focal epilepsy with deleterious mutations found in a wide range of inherited forms of focal epilepsy, associated with malformation of cortical development in certain cases. Identification of frameshift, truncation, and deletion mutations implicates haploinsufficiency of DEPDC5 in the etiology of focal epilepsy. DEPDC5 is a component of the GATOR1 complex, acting as a negative regulator of mTOR signaling.MethodsZebrafish represents a vertebrate model suitable for genetic analysis and drug screening in epilepsy‐related disorders. In this study, we defined the expression of depdc5 during development and established an epilepsy model with reduced Depdc5 expression.ResultsHere we report a zebrafish model of Depdc5 loss‐of‐function that displays a measurable behavioral phenotype, including hyperkinesia, circular swimming, and increased neuronal activity. These phenotypic features persisted throughout embryonic development and were significantly reduced upon treatment with the mTORC1 inhibitor, rapamycin, as well as overexpression of human WT DEPDC5 transcript. No phenotypic rescue was obtained upon expression of epilepsy‐associated DEPDC5 mutations (p.Arg487* and p.Arg485Gln), indicating that these mutations cause a loss of function of the protein.InterpretationThis study demonstrates that Depdc5 knockdown leads to early‐onset phenotypic features related to motor and neuronal hyperactivity. Restoration of phenotypic features by WT but not epilepsy‐associated Depdc5 mutants, as well as by mTORC1 inhibition confirm the role of Depdc5 in the mTORC1‐dependent molecular cascades, defining this pathway as a potential therapeutic target for DEPDC5‐inherited forms of focal epilepsy.

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Section: Resultssupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Depdc5 knockdown causes mTOR‐dependent motor hyperactivity in zebrafish

Calbiac

Dabacan²,

Marsan

et al. 2018

Ann Clin Transl Neurol

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“…It combines easy handling and relatively high-throughput screening with the complexity of a whole vertebrate organism. Within the past decade, the usefulness of zebrafish in epilepsy research has been validated through studies involving pharmacologically induced acute seizure models [13][14][15] as well as zebrafish models of genetic epileptic syndromes (Angelman's [16], Lowe's [17], BNFC [18], EAST [19], and Dravet [20,21]). More recently, some of these zebrafish models have been applied in high-throughput epilepsy drug discovery (PTZ [22] and Dravet [20]).…”

Section: Introductionmentioning

confidence: 99%

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

Leclercq

Afrikanova

Langlois

et al. 2015

Epilepsy & Behavior

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Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be timeconsuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (D,L)-Allylglycine inhibits glutamic acid decarboxylase (GAD) -the key enzyme in γ-aminobutyric acid (GABA) biosynthesis -leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD 50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated crossspecies similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures.

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“…Zebrafish is also a good model for studying anxiety and stress, with well-validated assays for novelty-and conflict-induced anxiety, social interaction, and antipredatory behavior (Gerlai, 2010;Maximino, Marques, et al, 2010;Oliveira, 2013). Importantly for EtOH withdrawal, seizure-like phenotypes were also characterized in the species (Hortopan, Dinday, & Baraban, 2010).…”

Section: Introductionmentioning

confidence: 99%

Behavioral and biochemical effects of ethanol withdrawal in zebrafish

Chaves

Felicio

Costa

et al. 2017

Preprint

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Chronic alcohol use induces adaptations and toxicity that can induce symptoms of anxiety, autonomic hyperarousal, and seizures when alcohol is removed (withdrawal syndrome).Zebrafish has recently gained wide attention as a behavioral model to study the neurobehavioral effects of acute and chronic alcohol use, including withdrawal. The literature, however, is very contradictory on findings regarding withdrawal effects, with some studies reporting increased anxiety, while others report no effect. A meta-analytic approach was taken to find the sources of this heterogeneity, and ethanol concentration during exposure and exposure duration were found to be the main sources of variation. A conceptual replication was also made using continuous exposure for 16 days in waterborne ethanol (0.5%) and assessing anxiety-like behavior in the light/dark test after 60 min withdrawal. Withdrawal was shown to reduce preference for darkness, consistent with decreased anxiety, but to increase risk assessment, consistent with increased anxiety. Animals were also subjected to the withdrawal protocol and injected with pilocarpine in a sub-convulsive dose to assess susceptibility to seizures. The protocol was sufficient to increase susceptibility to seizures in animals exposed to ethanol. Finally, withdrawal also decreased catalase activity in the brain, but not in the head kidney, suggesting that oxidative stress could be a mechanism associated with the behavioral effects of ethanol withdrawal.

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Zebrafish as a model for studying genetic aspects of epilepsy

Cited by 147 publications

References 49 publications

Depdc5 knockdown causes mTOR‐dependent motor hyperactivity in zebrafish

Depdc5 knockdown causes mTOR‐dependent motor hyperactivity in zebrafish

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

Behavioral and biochemical effects of ethanol withdrawal in zebrafish

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