A Missense Mutation of the Gene Encoding Voltage-Dependent Sodium Channel (Na<sub>v</sub>1.1) Confers Susceptibility to Febrile Seizures in Rats

Mashimo, Tomoji; Ohmori, Iori; Ouchida, Mamoru; Ohno, Yukihiro; Tsurumi, Toshiko; Miki, Takafumi; Wakamori, Minoru; Ishihara, Shizuka; Yoshida, Takashi; Takizawa, Akiko; Kato, Megumi; Hirabayashi, Masumi; Sasa, Masashi; Mori, Yasuo; Serikawa, Tadao

doi:10.1523/jneurosci.3360-09.2010

Cited by 63 publications

(53 citation statements)

References 42 publications

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“…Age-dependent susceptibility to hyperthermia-induced seizures were identified in the Scn1a mouse model of DS (Oakley et al 2009) and these seizures were alleviated with the combined therapy of the anti-seizure drugs clonazepam and tiagabine (Oakley et al 2013). The Scn1a GEFS+ rat model (Hiss) demonstrated increased susceptibility to acutely induced hyperthermia seizures (Mashimo et al 2010), which resulted in activation of the limbic system (Ohno et al 2011). However, prolonged or repetitive FSs induced between 3 and 5 weeks of age in this model did not result in seizures in the adults (Mashimo et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

Dutton

Dutt

Papale

et al. 2017

Experimental Neurology

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Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A, encoding the Nav1.1 channel, are responsible for a number of epilepsy disorders including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS). Patients with SCN1A mutations often experience prolonged early-life febrile seizures (FSs), raising the possibility that these events may influence epileptogenesis and lead to more severe adult phenotypes. To test this hypothesis, we subjected 21-23-day-old mice expressing the human SCN1A GEFS+ mutation R1648H to prolonged hyperthermia, and then examined seizure and behavioral phenotypes during adulthood. We found that early-life FSs resulted in lower latencies to induced seizures, increased severity of spontaneous seizures, hyperactivity, and impairments in social behavior and recognition memory during adulthood. Biophysical analysis of brain slice preparations revealed an increase in epileptiform activity in CA3 pyramidal neurons along with increased action potential firing, providing a mechanistic basis for the observed worsening of adult phenotypes. These findings demonstrate the long-term negative impact of early-life FSs on disease outcomes. This has important implications for the clinical management of this patient population and highlights the need for therapeutic interventions that could ameliorate disease progression.

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Section: Discussionmentioning

confidence: 99%

Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

Dutton

Dutt

Papale

et al. 2017

Experimental Neurology

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“…Furthermore, missense mutations in the Na V 1.1 / SCN1A gene have been identified in GEFS+ patients. In one of the most common mutations, the Na + channel inactivation curve is left-shifted, which will reduce the number of available Na + channels (114). Thus, we increasingly understand the relations between the fast signaling properties of PV + interneurons and a neurological disease phenotype.…”

Section: Role Of Pvmentioning

confidence: 99%

Fast-spiking, parvalbumin ⁺ GABAergic interneurons: From cellular design to microcircuit function

Gan

Jónás

2014

Science

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1,001

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Review summary (print version)Background Fast-spiking, parvalbumin-expressing interneurons (PV + interneurons) play a key role in several functions of the brain. They contribute to feedback and feedforward inhibition, and are critically involved in the generation of network oscillations. A hallmark property of these interneurons is speed. In essence, these cells convert an excitatory input signal into an inhibitory output signal within a millisecond. How these remarkable signaling properties are implemented at the molecular and cellular level has been unclear. Furthermore, how PV + interneurons shape complex network functions has remained an open question. Advances Outlook PV+ interneurons may also play a key role in numerous brain diseases. These include epilepsy, but also complex psychiatric diseases, such as schizophrenia. Thus, PV + interneurons may become important therapeutic targets in the future. However, much needs to be learned about the basic function of these interneurons before clinical neuroscientists will have a chance to successfully use PV + interneurons for therapeutic purposes. 3 Full article (online) AbstractThe success story of fast-spiking, parvalbumin-expressing (PV + ) GABAergic interneurons is amazing. In 1995, the properties of these interneurons were completely unknown. 20 years later, thanks to the massive use of subcellular patchclamp techniques, simultaneous multiple-cell recording, optogenetics, in vivo measurements, and computational approaches, our knowledge about PV + interneurons became more extensive than for several types of pyramidal neurons (Box 1). These findings have implications beyond the "small world" of basic research on GABAergic cells. For example, the results provide a first proof of principle that neuroscientists might be able to close the gaps between molecular, cellular, network, and behavioral level, which represents one of the main challenges at the present time. Furthermore, the results may form the basis for using PV + interneurons as therapeutical targets for brain diseases in the future. However, much needs to be learned about the basic function of these interneurons before clinical neuroscientists will be able to use PV + interneurons for therapeutic purposes.

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“…Surgical procedures for the electrode implantation and EEG recordings were performed as described previously (20,22). Since it was confirmed in the preliminary experiments that both male and female rats exhibited SWD with a similar frequency, GRY rats of either sex (250 -350 g) were employed.…”

Section: Drug Treatments and Eeg Recordingmentioning

confidence: 99%

Serotonergic Modulation of Absence-Like Seizures in Groggy Rats: a Novel Rat Model of Absence Epilepsy

et al. 2010

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Abstract.To explore the role of the serotonergic system in modulating absence seizures, we examined the effects of 5-HT 1A and 5-HT 2 agonists on the incidence of spike-and-wave discharges (SWD) in Groogy (GRY) rats, a novel rat model of absence-like epilepsy. GRY rats exhibited spontaneous absence-like seizures characterized by the incidence of sudden immobile posture and synchronously-associated SWD. The total duration of SWD in GRY rats was about 300 -400 s/15-min observation period under the control conditions. However, the incidence of SWD was markedly reduced either by the 5-HT 1A agonist (±)-8-hydroxy-2-(di-n-propylamino)-tetralin [(±)8-OH-DPAT] or the 5-HT 2 agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)DOI]. The 5-HT reuptake inhibitors, fluoxetine and clomipramine, also inhibited the SWD generation. In addition, the inhibitory effects of (±)8-OH-DPAT and (±)DOI were reversed by WAY-100135 (5-HT 1A antagonist) and ritanserin (5-HT 2 antagonist), respectively. The present results suggest that the serotonergic system negatively regulates the incidence of absence seizures by stimulation of 5-HT 1A and 5-HT 2 receptors.

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A Missense Mutation of the Gene Encoding Voltage-Dependent Sodium Channel (Na_v1.1) Confers Susceptibility to Febrile Seizures in Rats

Cited by 63 publications

References 42 publications

Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

Fast-spiking, parvalbumin ⁺ GABAergic interneurons: From cellular design to microcircuit function

Serotonergic Modulation of Absence-Like Seizures in Groggy Rats: a Novel Rat Model of Absence Epilepsy

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A Missense Mutation of the Gene Encoding Voltage-Dependent Sodium Channel (Nav1.1) Confers Susceptibility to Febrile Seizures in Rats

Cited by 63 publications

References 42 publications

Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

Fast-spiking, parvalbumin + GABAergic interneurons: From cellular design to microcircuit function

Serotonergic Modulation of Absence-Like Seizures in Groggy Rats: a Novel Rat Model of Absence Epilepsy

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A Missense Mutation of the Gene Encoding Voltage-Dependent Sodium Channel (Na_v1.1) Confers Susceptibility to Febrile Seizures in Rats

Fast-spiking, parvalbumin ⁺ GABAergic interneurons: From cellular design to microcircuit function