Epilepsy in the Developing Brain: Lessons from the Laboratory and Clinic

Holmes, Gregory L.

doi:10.1111/j.1528-1157.1997.tb01074.x

Cited by 256 publications

(155 citation statements)

References 227 publications

(176 reference statements)

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“…Despite dramatically lower synaptic connectivity (Bayer, 1980;Gomez-Di Cesare et al, 1997), the immature brain is much more susceptible to seizures than the adult brain (DeLorenzo et al, 1992;Holmes, 1997). Modeling studies clearly indicate that synchronous activity is not easily maintained when synaptic connectivity is low (Traub and Miles, 1991).…”

Section: Introductionmentioning

confidence: 99%

Excitatory Actions of Endogenously Released GABA Contribute to Initiation of Ictal Epileptiform Activity in the Developing Hippocampus

2003

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In the developing rat hippocampus, ictal epileptiform activity can be elicited easily in vitro during the first three postnatal weeks. Changes in neuronal ion transport during this time cause the effects of GABA A receptor (GABA A -R) activation to shift gradually from strongly depolarizing to hyperpolarizing. It is not known whether the depolarizing effects of GABA and the propensity for ictal activity are causally linked. A key question is whether the GABA-mediated depolarization is excitatory, which we defined operationally as being sufficient to trigger action potentials. We assessed the effect of endogenous GABA on ictal activity and neuronal firing rate in hippocampal slices from postnatal day 1 (P1) to P30. In extracellular recordings, there was a strong correlation between the postnatal age at which GABA A -R antagonists decreased action potential frequency (P23) and the age at which ictal activity could be induced by elevated potassium (P23). In addition, there was a strong correlation between the fraction of slices in which ictal activity was induced by elevated potassium concentrations and the fractional decrease in action potential firing when GABA A -Rs were blocked in the presence of ionotropic glutamate receptor antagonists. Finally, ictal activity induced by elevated potassium was blocked by the GABA A -R antagonists bicuculline and SR-95531 (gabazine) and increased in frequency and duration by GABA A -R agonists isoguvacine and muscimol. Thus, the propensity of the developing hippocampus for ictal activity is highly correlated with the effect of GABA on action potential probability and reversed by GABA A antagonists, indicating that GABA-mediated excitation is causally linked to ictal activity in this developmental window.

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Section: Introductionmentioning

confidence: 99%

Excitatory Actions of Endogenously Released GABA Contribute to Initiation of Ictal Epileptiform Activity in the Developing Hippocampus

2003

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“…8 for a recent review). This concept is supported in the human by the much greater incidence of seizures in the infant and young child, as compared with the adult 1,2,9 .…”

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“…Enhanced excitability and a higher sensitivity to proconvulsant agents have also been demonstrated in immature experimental animals, including rats, cats and monkeys 10,11 . Several characteristics of developing neuronal circuitry might account for this enhanced excitability 8,12 . For example, GABA, the principal inhibitory neurotransmitter in the mature CNS, has depolarizing, and thus excitatory, properties during the first postnatal week in the rat 12,13 .…”

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confidence: 99%

“…In addition, excitatory amino acid receptors are both more abundant in the immature brain 14 and possess a subunit makeup that promotes neuronal depolarization 15 . These factors are thought to contribute to an altered excitation-inhibition balance during development 8 . At the circuit level, increased neuronal excitability is evident, leading, for example, to the robust long-term potentiation observed during the second postnatal week ('infancy' in the rat) in both hippocampal and cortical synapses 16,17 .…”

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confidence: 99%

“…In addition, the number of cortical and hippocampal excitatory synapses is highest during this period and decreases after the third post-natal week 18 . All of these factors favor enhanced excitation and a propensity to generation and propagation of seizures 8 .…”

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confidence: 99%

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Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain

Baram

Hatalski

1998

Trends in Neurosciences

198

251

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Most human seizures occur early in life, consistent with established excitability-promoting features of the developing brain. Surprisingly, the majority of developmental seizures are not spontaneous but are provoked by injurious or stressful stimuli. What mechanisms mediate 'triggering' of seizures and limit such reactive seizures to early postnatal life? Recent evidence implicates the excitatory neuropeptide, corticotropin-releasing hormone (CRH). Stress activates expression of the CRH gene in several limbic regions, and CRH-expressing neurons are strategically localized in the immature rat hippocampus, in which this neuropeptide increases the excitability of pyramidal cells in vitro. Indeed, in vivo, activation of CRH receptors -maximally expressed in hippocampus and amygdala during the developmental period which is characterized by peak susceptibility to 'provoked' convulsions -induces severe, age-dependent seizures. Thus, converging data indicate that activation of expression of CRH constitutes an important mechanism for generating developmentally regulated, triggered seizures, with considerable clinical relevance.The majority of seizures occurring in the developing human are not spontaneous, that is, they are not related to inherent abnormalities in the balance of neuronal excitation and inhibition 1 . Rather, most seizures during infancy and childhood are provoked or triggered by alterations in the normal milieu of excitable neurons 2 . Thus, rapid triggering by fever, hypoxia or trauma provokes the majority of seizures in the infant and young child. These seizures -a manifestation of rapid and transient enhancement of neuronal excitability in response to adverse and potentially injurious agents -demonstrate an exquisite age specificity (Table 1): febrile seizures are exclusive to infancy and early childhood 1,2 , immediate traumatic seizures (as opposed to posttraumatic epilepsy) are far more common in the young human compared with the adult, and anoxia-related seizures occur primarily in the full-term neonate 5,7 . Other seizures that are not genetic in origin, such as infantile spasms, which have been linked to a large number of injuries of the CNS and stressors that include infections and malformations, are highly age specific and primarily restricted to the first year of life 6 .In the present review, we focus on novel and evolving concepts regarding potential mechanisms for the rapid transduction of stressful alterations of neuronal milieu into enhanced excitability and resulting seizures. We discuss the cascade of molecular events triggered by 'stress', with an emphasis on the excitatory neuropeptide, corticotropinreleasing hormone (CRH). Established and novel in vivo and in vitro evidence for the role of CRH in enhancing excitation in key limbic circuits, particularly in the tri-synaptic hippocampal pathway, are discussed. Finally, we describe recent data regarding the receptors that mediate CRH-induced excitation, and provide the probable mechanisms underlying the remarkable age specificit...

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