GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy

Koyama, Ryuta; Tao, Kentaro; Sasaki, Takuya; Ichikawa, Junya; Miyamoto, Daisuke; Muramatsu, Rieko; Matsuki, Norio; Ikegaya, Yuji

doi:10.1038/nm.2850

Cited by 152 publications

(155 citation statements)

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“…As bumetanide is rapidly eliminated in rodents and only poorly penetrates into the brain [60], we are currently trying to overcome these disadvantages by either administering more lipophilic prodrugs of bumetanide or inhibiting its metabolism in rodents, or both. Interestingly, the lack of any significant effects of single drug treatment with bumetanide in our study [60] may be due to the model (pilocarpine) used because in a more recent study by Koyama et al [62] bumetanide was shown to prevent the development of epilepsy after febrile seizures in rats. Thus, again, the type and severity of epileptogenic brain insult is important when studying the antiepileptogenic efficacy of compounds.…”

Section: Examples For Synergistic Drug Combinationsmentioning

confidence: 63%

“…Other potential targets include NKCC1 [57,62] and modulators of neuroinflammation, that is, IL-1, COX-2, and transforming growth factor β [63]. Further interesting findings (not discussed in detail here) include 1) administration of decoy oliognucleotides limiting the transcriptional repressor, neuron-restrictive silencer factor (NRSF), which is initiated after SE, resulted in a 70 % reduction in the number of SRS during the ensuing 2 weeks [65]; 2) pharmacological depletion of a microRNA, miR-134, initiated after SE reduced the occurrence of SRS when tested weeks later [66]; and 3) treatment with atipamezole, an α2-adrenergic receptor antagonist, starting 1 week after SE, reduced frequency and severity of SRS tested after wash-out from atipamezole, indicating a disease-modifying effect [67].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.

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Section: Examples For Synergistic Drug Combinationsmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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“…GABAergically-induced ectopic granule cells in the dentate gyrus during development in FS rats [29] ); and (2) a decrease in HCN (hyperpolarization-activated cyclic nucleotide-gated) channels, which are associated with hippocampal rhythms [31,32] , induced by FSs during epileptogenesis [30] . Here we found that the CA3 pyramidal neuronal cell body circumference occupied by inhibitory presynaptic terminals was significantly increased in FS rats at P35.…”

Section: Discussionmentioning

confidence: 99%

Early hypoactivity of hippocampal rhythms during epileptogenesis after prolonged febrile seizures in freely-moving rats

et al. 2015

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Prospective and experimental studies have shown that individuals with early-life complex/prolonged febrile seizures (FSs) have a high incidence of temporal lobe epilepsy during adulthood, revealing a close relationship between FSs and epilepsy. However, little is known about how epileptogenesis develops after FSs. The present study was designed to investigate acquired seizure susceptibility and analyze local field potentials during the latent period after FSs. We found that the seizure susceptibility decreased in 35-day-old (P35) FS rats but increased in P60 FS rats. Consistently, hippocampal electroencephalogram (EEG) power in every band was decreased at P35 but increased at P60 in FS rats. Our results provide direct evidence for hypoactivity but not hyperactivity during the early phase of the latent period, displaying a broad decrease in hippocampal rhythms. These characteristic EEG changes can be a useful biomarker for the early diagnosis of epileptogenesis induced by FSs.

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“…Bumetanide has also shown promise in preventing epileptogenesis in other animal models with postnatal human correlates, including febrile seizures leading to subsequent temporal lobe epilepsy (8). While this may be a more readily translatable use of bumetanide, establishing this approach as a treatment for epileptogenesis poses other challenges.…”

Section: Nurture Trumps Nature In a Model Of Heritable Epilepsy: Willmentioning

confidence: 99%

Nurture Trumps Nature in a Model of Heritable Epilepsy: Will Bumetanide be the First Antiepileptogenic Drug?

Heuermann¹,

Chetkovich²

2016

Epilepsy Curr

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CommentaryCurrently available antiepileptic drugs, while life-changing for millions of patients, are far from perfect. Many patients fail to achieve full seizure remission despite trials of several drugs or experience intolerable side effects. Even when successful, treatment is often lifelong, doing little to reverse the underlying pathological changes that lead to seizure generation. These limitations are particularly salient in neonatal and pediatric epilepsy syndromes, which are often refractory to treatment and associated with devastating cognitive delay or regression (1). One of the foremost goals of epilepsy research is thus to identify the cellular and network perturbations that produce recurrent seizures, in hopes of finding new interventions to prevent or reverse the process of epileptogenesis.Marguet and colleagues used a transgenic mouse line expressing a dominant-negative Kv7.2 subunit (KCNQ2 G279S ) throughout the brain. Kv7 channels pass a noninactivating current (I M ) that regulates neuronal excitability and firing patterns (2). The KCNQ2 G279S mice have dramatic reductions in I M and consequent hyperexcitability of hippocampal pyramidal neurons (and likely cortical neurons, as well). A prior study noted frequent focal seizures in these mice with tonic limb or neck extension, and occasional generalized tonic-clonic seizures (3). Intriguingly, suppressing KCNQ2 G279S expression during a "critical period" of the first 2 postnatal weeks (using a tetracycline-suppressible expression system engineered into these mice) prevented behavioral seizures and pathological changes in the hippocampus later in life.Marguet and colleagues now build upon these findings with a more clinically relevant paradigm, using the loop diuretic bumetanide during the same critical period to prevent the development of seizures in adult KCNQ2 G279S mice. The rationale for using bumetanide, an inhibitor of the NKCC1 cotransporter, is that GABA exerts an excitatory rather than inhibitory effect during the first postnatal week in mice as a result of the high intracellular chloride levels established by NKCC1 (4, 5). Subsequent upregulation of the potassiumchloride cotransporter KCC2 counteracts this effect, extruding Cl − and establishing the more familiar inhibitory role of GABA A receptors. The authors hypothesized that bumetanide treatment during the first 2 postnatal weeks would reduce the excitatory action of GABA, dampen overall network excitability, and perhaps counteract the pro-excitatory effects of KCNQ2 G279S expression. The study began by confirming that CA1 pyramidal neurons of the mutant mice indeed lack I M during the postnatal critical period and are therefore hyperexcitable in response to depolarizing current injections. In vivo single-unit recordings also showed an increased propensity for burst firing in mutant The nervous system is vulnerable to perturbations during specific developmental periods. Insults during such susceptible time windows can have long-term consequences, including the development of neurolog...

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GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy

Cited by 152 publications

References 58 publications

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Early hypoactivity of hippocampal rhythms during epileptogenesis after prolonged febrile seizures in freely-moving rats

Nurture Trumps Nature in a Model of Heritable Epilepsy: Will Bumetanide be the First Antiepileptogenic Drug?

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