Synergistic GABA-Enhancing Therapy against Seizures in a Mouse Model of Dravet Syndrome

Oakley, John C.; Cho, Alvin R.; Cheah, Christine S.; Scheuer, Todd; Catterall, William A.

doi:10.1124/jpet.113.203331

Cited by 49 publications

(40 citation statements)

References 50 publications

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“…Similar to DS patients, all DS/B6 mice had myoclonic seizures preceding their thermally induced GTC seizure (Fig. 1B (Oakley et al, 2013)). In contrast, 30% of DS/129 mice did not have myoclonic seizures (Fig.…”

Section: Resultsmentioning

confidence: 68%

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Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome

Rubinstein¹,

Westenbroek²,

Yu³

et al. 2015

Neurobiology of Disease

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119

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Dominant loss-of-function mutations in voltage-gated sodium channel NaV1.1 cause Dravet Syndrome, an intractable childhood-onset epilepsy. NaV1.1+/− Dravet Syndrome mice in C57BL/6 genetic background exhibit severe seizures, cognitive and social impairments, and premature death. Here we show that Dravet Syndrome mice in pure 129/SvJ genetic background have many fewer seizures and much less premature death than in pure C57BL/6 background. These mice also have a higher threshold for thermally induced seizures, fewer myoclonic seizures, and no cognitive impairment, similar to patients with Genetic Epilepsy with Febrile Seizures Plus. Consistent with this mild phenotype, mutation of NaV1.1 channels has much less physiological effect on neuronal excitability in 129/SvJ mice. In hippocampal slices, the excitability of CA1 Stratum Oriens interneurons is selectively impaired, while the excitability of CA1 pyramidal cells is unaffected. NaV1.1 haploinsufficiency results in increased rheobase and threshold for action potential firing and impaired ability to sustain high-frequency firing. Moreover, deletion of NaV1.1 markedly reduces the amplification and integration of synaptic events, further contributing to reduced excitability of interneurons. Excitability is less impaired in inhibitory neurons of Dravet Syndrome mice in 129/SvJ genetic background. Because specific deletion of NaV1.1 in forebrain GABAergic interneuons is sufficient to cause the symptoms of Dravet Syndrome in mice, our results support the conclusion that the milder phenotype in 129/SvJ mice is caused by lesser impairment of sodium channel function and electrical excitability in their forebrain interneurons. This mild impairment of excitability of interneurons leads to a milder disease phenotype in 129/SvJ mice, similar to Genetic Epilepsy with Febrile Seizures Plus in humans.

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Section: Resultsmentioning

confidence: 68%

“…Thermal induction of seizures was performed as described previously (Oakley et al, 2013; Oakley et al, 2009). Body temperature was measured continuously with a rectal temperature probe and controlled to ± 0.3 °C with a feedback temperature controller (TCAT2DF; Physitemp, Clifton, NJ) and heat lamp.…”

Section: Methodsmentioning

confidence: 99%

Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome

Rubinstein¹,

Westenbroek²,

Yu³

et al. 2015

Neurobiology of Disease

Self Cite

119

View full text Add to dashboard Cite

show abstract

“…However, mice with deletion of Na v 1.1 in all forebrain interneurons recapitulated all the epileptic symptoms (Yu et al, 2006;Oakley et al, 2009Oakley et al, , 2013Kalume et al, 2013), hyperactivity, reduced sociability and cognitive deficits Han et al, 2012). In contrast, not all of these symptoms were observed in comparable severity in PV&SST-DS mice.…”

Section: Contribution Of Other Interneurons To Dravet Syndromementioning

confidence: 92%

Dissecting the phenotypes of Dravet syndrome by gene deletion

Rubinstein

Han

Tai

et al. 2015

Brain

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114

139

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*These authors contributed equally to this work.Neurological and psychiatric syndromes often have multiple disease traits, yet it is unknown how such multi-faceted deficits arise from single mutations. Haploinsufficiency of the voltage-gated sodium channel Na v 1.1 causes Dravet syndrome, an intractable childhood-onset epilepsy with hyperactivity, cognitive deficit, autistic-like behaviours, and premature death. Deletion of Na v 1.1 channels selectively impairs excitability of GABAergic interneurons. We studied mice having selective deletion of Na v 1.1 in parvalbumin-or somatostatin-expressing interneurons. In brain slices, these deletions cause increased threshold for action potential generation, impaired action potential firing in trains, and reduced amplification of postsynaptic potentials in those interneurons. Selective deletion of Na v 1.1 in parvalbumin-or somatostatin-expressing interneurons increases susceptibility to thermally-induced seizures, which are strikingly prolonged when Na v 1.1 is deleted in both interneuron types. Mice with global haploinsufficiency of Na v 1.1 display autistic-like behaviours, hyperactivity and cognitive impairment. Haploinsufficiency of Na v 1.1 in parvalbuminexpressing interneurons causes autistic-like behaviours, but not hyperactivity, whereas haploinsufficiency in somatostatin-expressing interneurons causes hyperactivity without autistic-like behaviours. Heterozygous deletion in both interneuron types is required to impair long-term spatial memory in context-dependent fear conditioning, without affecting short-term spatial learning or memory. Thus, the multi-faceted phenotypes of Dravet syndrome can be genetically dissected, revealing synergy in causing epilepsy, premature death and deficits in long-term spatial memory, but interneuron-specific effects on hyperactivity and autistic-like behaviours. These results show that multiple disease traits can arise from similar functional deficits in specific interneuron types.

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“…At the electrophysiological level, clonazepam increased sIPSC amplitude, which leads to a decrease in sEPSC frequency. Chronic treatment with a combination of the clonazepam and the GABA reuptake inhibitor tiagabine had a synergistic effect on seizure control (Oakley et al, 2013).…”

Section: Rett Syndromementioning

confidence: 97%

The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders

Braat

Kooy

2015

Neuron

254

214

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Intellectual disability, autism spectrum disorder, and epilepsy are prime examples of neurodevelopmental disorders that collectively affect a significant percentage of the world population. Recent technological breakthroughs allowed the elucidation of the genetic causes of many of these disorders. As neurodevelopmental disorders are genetically heterogeneous, the development of rational therapy is extremely challenging. Fortunately, many causative genes are interconnected and cluster in specific cellular pathways. Targeting a common node in such a network would allow us to interfere with a series of related neurodevelopmental disorders at once. Here, we argue that the GABAergic system is disturbed in many neurodevelopmental disorders, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and is a key candidate target for therapeutic intervention. Many drugs that modulate the GABAergic system have already been tested in animal models with encouraging outcomes and are readily available for clinical trials.

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Synergistic GABA-Enhancing Therapy against Seizures in a Mouse Model of Dravet Syndrome

Abstract: Seizures remain uncontrolled in 30% of patients with epilepsy,

Cited by 49 publications

References 50 publications

Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome

Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome

Dissecting the phenotypes of Dravet syndrome by gene deletion

The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders

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