NKCC1 transporter facilitates seizures in the developing brain

Dzhala, Volodymyr; Talos, Delia M.; Sdrulla, Dan A; Brumback, Audrey C.; Mathews, Gregory C.; Benke, Tim A.; Delpire, Eric; Jensen, Frances E.; Staley, Kevin J.

doi:10.1038/nm1301

Cited by 873 publications

(1,017 citation statements)

References 49 publications

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“…Second, [Cl − ] i accumulation is caused (at least in immature neurons) by the activation of NKCC1 cotransporter that imports Na + , K + , and Cl − (Achilles et al, 2007;Sipilä et al, 2009). As discussed in Section 9, this mechanism may play an important role in neonatal seizures (Dzhala et al, 2005(Dzhala et al, , 2010Nardou et al, 2009). Third, GABA A receptormediated depolarizations are contributed by HCO 3 − currents that have quite positive reversal potentials (−10 to −15 mV) (Staley et al, 1995;Lamsa and Kaila, 1997;Kaila et al, 1993Kaila et al, , 1997Rivera et al, 2005).…”

Section: Gaba a Receptor-mediated Depolarizing Actionsmentioning

confidence: 98%

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Avoli¹,

Curtis²

2011

Progress in Neurobiology

227

253

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GABA is the main inhibitory neurotransmitter in the adult forebrain, where it activates ionotropic type A and metabotropic type B receptors. Early studies have shown that GABA A receptormediated inhibition controls neuronal excitability and thus the occurrence of seizures. However, more complex, and at times unexpected, mechanisms of GABAergic signaling have been identified during epileptiform discharges over the last few years. Here, we will review experimental data that point at the paradoxical role played by GABA A receptor-mediated mechanisms in synchronizing neuronal networks, and in particular those of limbic structures such as the hippocampus, the entorhinal and perirhinal cortices, or the amygdala. After having summarized the fundamental characteristics of GABA A receptor-mediated mechanisms, we will analyze their role in the generation of network oscillations and their contribution to epileptiform synchronization. Whether and how GABA A receptors influence the interaction between limbic networks leading to ictogenesis will be also reviewed. Finally, we will consider the role of altered inhibition in the human epileptic brain along with the ability of GABA A receptor-mediated conductances to generate synchronous depolarizing events that may lead to ictogenesis in human epileptic disorders as well.

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Section: Gaba a Receptor-mediated Depolarizing Actionsmentioning

confidence: 98%

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Avoli¹,

Curtis²

2011

Progress in Neurobiology

227

253

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“…However, caution is warranted as work from our lab has also shown that 17β-estradiol may exacerbate developmental injuries with underlying GABA A receptor involvement. These include fetal alcohol syndrome and seizures (Dzhala et al, 2005;Galindo et al, 2005;Khalilov et al, 2005;Young et al, 2005). While 17β-estradiol exerts substantial neuroprotection from hypoxia/ischemia, the benefit it confers may be dependent upon the type of injury and the age of the infant.…”

Section: Discussionmentioning

confidence: 99%

17β-Estradiol protects the neonatal brain from hypoxia–ischemia

Nuñez

Yang²,

Jiang³

et al. 2007

Experimental Neurology

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Hypoxia-ischemia is relatively common in human infants. Hypoxia-ischemia can occur as a result of complications associated with prematurity or birth, frequently leading to altered brain development and cognitive and behavioral deficits that persist throughout life. Despite the relative frequency of neonatal hypoxic ischemic encephalopathy, the immature brain sustains relatively less damage than an adult who experiences a similar crisis of oxygen and nutrient deprivation. Therefore, factors may be present that protect the developing brain. During late gestation, the infant brain encounters high levels of the steroid hormone 17β-estradiol. This observation, combined with evidence supporting 17β-estradiol as a neuroprotective agent, led us to hypothesize that increasing the basal level of 17β-estradiol would reduce the amount of hypoxia-ischemia induced injury to the neonatal brain. To test that hypothesis we administered 17β-estradiol using either a repeated dosing paradigm or a single dose paradigm to immature male and female rats. Here we show that the repeated dosing paradigm (three doses of 17β-estradiol) provided approximately 70% protection of the hippocampus, basal ganglia, and amygdala. By contrast, a single administration of 17β-estradiol 24 hours prior to hypoxia-ischemia conferred little protection. The only exception was the pyramidal layer of the female hippocampus, which was modestly protected (16% reduction in damage). The protection afforded by the multiple administrations of 17β-estradiol was similar for females and males, with the only exception being the male amygdala, which displayed less damage than the female amgydala. We conclude that 17β-estradiol acts as a potent neuroprotective agent against hypoxia-ischemia induced damage to the developing brain, and that pretreating infants at risk for hypoxic ischemic injury may be advisable.

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“…In contrast, during the very early stages of development (prenatal-early neonatal), Cl -flow is regulated by the inward NKCC1, which increases concentrations of intracellular Cl - [121]. As a result, during early stages of development, the GABA-A receptor-mediated opening of Cl -channels leads to an outward Cl -flow and, thus, to excitation [122]. One of the presumed consequences of GABA acting as an excitatory neurotransmitter early in life is the ineffectiveness of GABAergic antiepileptic drugs [122,123] on the one hand, and the antiepileptic effects of NKCC1 blockers on the other hand.…”

Section: Rapid Kindling: a Model Of Epileptogenesis In The Developingmentioning

confidence: 99%

“…As a result, during early stages of development, the GABA-A receptor-mediated opening of Cl -channels leads to an outward Cl -flow and, thus, to excitation [122]. One of the presumed consequences of GABA acting as an excitatory neurotransmitter early in life is the ineffectiveness of GABAergic antiepileptic drugs [122,123] on the one hand, and the antiepileptic effects of NKCC1 blockers on the other hand. Indeed, the NKCC1 blocker bumetanide exerted acute anticonvulsant effects in immature animals [123].…”

Section: Rapid Kindling: a Model Of Epileptogenesis In The Developingmentioning

confidence: 99%

Novel Animal Models of Pediatric Epilepsy

et al. 2012

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When mimicking epileptic processes in a laboratory setting, it is important to understand the differences between experimental models of seizures and epilepsy. Because human epilepsy is defined by the appearance of multiple spontaneous recurrent seizures, the induction of a single acute seizure without recurrence does not constitute an adequate epilepsy model. Animal models of epilepsy might be useful for various tasks. They allow for the investigation of pathophysiological mechanisms of the disease, the evaluation, or the development of new antiepileptic treatments, and the study of the consequences of recurrent seizures and neurological and psychiatric comorbidities. Although clinical relevance is always an issue, the development of models of pediatric epilepsies is particularly challenging due to the existence of several key differences in the dynamics of human and rodent brain maturation. Another important consideration in modeling pediatric epilepsy is that "children are not little adults," and therefore a mere application of models of adult epilepsies to the immature specimens is irrelevant. Herein, we review the models of pediatric epilepsy. First, we illustrate the differences between models of pediatric epilepsy and models of the adulthood consequences of a precipitating insult in early life. Next, we focus on new animal models of specific forms of epilepsies that occur in the developing brain. We conclude by emphasizing the deficiencies in the existing animal models and the need for several new models.

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NKCC1 transporter facilitates seizures in the developing brain

Cited by 873 publications

References 49 publications

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

17β-Estradiol protects the neonatal brain from hypoxia–ischemia

Novel Animal Models of Pediatric Epilepsy

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