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Febrile seizures (FS) are the most common type of seizures in infants and preschool children. Inflammatory mediators, which are known triggers of fever, have also been implicated as contributors to the onset of these seizures. Evidence that inflammation is present following FS and during established epilepsy suggests that it could also influence epileptogenesis. However, the potential involvement of inflammatory mediators to the epileptogenic process that may follow prolonged FS has yet to be fully determined. This article reviews the current state of our knowledge and major gaps that remain by focusing on four questions: Does inflammation contribute to the generation of FS? Does prolonged FS or febrile status epilepticus (SE) cause temporal lobe epilepsy in the absence of predisposing factors? Does inflammation contribute to the process by which febrile SE causes limbic epilepsy? And finally, can inflammation be a foundation for biomarkers and therapy for FS-induced epileptogenesis?

The human brain is a tremendously complex and still enigmatic three-dimensional structure, composed of countless interconnected neurons and glia. The temporal evolution of the brain throughout life provides a fourth dimension, one that influences every element of the brain's function in health and disease. This temporal evolution contributes to the probability of seizure generation and to the type and the nature of these seizures. The age-specific properties of the brain also influence the consequences of seizures on neuronal structure and behavior. These, in turn, govern epileptic activity and cognitive and emotional functions, contributing to the diverse consequences of seizures and epilepsy throughout life.

Because epilepsy often occurs during development, understanding the mechanisms by which this process takes place (epileptogenesis) is important. In addition, the age-specificity of seizures and epilepsies of the neonatal, infancy, and childhood periods suggests that the processes and mechanisms that culminate in epilepsy might be age specific as well. Here we provide an updated review of recent and existing literature and discuss evidence that neuronal loss may occur during epileptogenesis in the developing brain, but is not required for the epileptogenic process. We speculate about the mechanisms for the resilience of neurons in immature limbic structures to epileptogenic insults, and propose that the type, duration and severity of these insults influence the phenomenology of the resulting spontaneous seizures.

The mechanisms that transform a normal brain to an epileptic one are not fully understood. Interleukin-1 beta (IL-1β) contributes to neuronal degeneration observed in several neurological disorders and recently has been implicated in neuronal injury that may accompany the process of epileptogenesis. This review presents the hypothesis that IL-1β may contribute to the development of epilepsy via several mechanisms, including classical effects on neuronal survival and transcription pathways; novel rapid effects on receptor-gated ion channels; and long-lasting effects on expression of selective gene families. Thus, evidence that IL-1β actions in epilepsy can be independent from the neurotoxic effects of this cytokine is presented.

Febrile seizures (FS) are the most common type of seizures in infants and preschool children. Inflammatory mediators, which are known triggers of fever, have also been implicated as contributors to the onset of these seizures. Evidence that inflammation is present following FS and during established epilepsy suggests that it could also influence epileptogenesis. However, the potential involvement of inflammatory mediators to the epileptogenic process that may follow prolonged FS has yet to be fully determined. This article reviews the current state of our knowledge and major gaps that remain by focusing on four questions: Does inflammation contribute to the generation of FS? Does prolonged FS or febrile status epilepticus (SE) cause temporal lobe epilepsy in the absence of predisposing factors? Does inflammation contribute to the process by which febrile SE causes limbic epilepsy? And finally, can inflammation be a foundation for biomarkers and therapy for FS-induced epileptogenesis?

Upregulated H-Current in Hyperexcitable CA1 Dendrites after Febrile Seizures. Dyhrfjeld-Johnsen J, Morgan RJ, Csaba Foldy, Soltesz I., Front Cell Neurosci. 2008;2:2. doi:10.3389/neuro.03.002.2008. Somatic recordings from CA1 pyramidal cells indicated a persistent upregulation of the h-current ( Ih) after experimental febrile seizures. Here, we examined febrile seizure-induced long-term changes in Ih and neuronal excitability in CA1 dendrites. Cell-attached recordings showed that dendritic Ih was significantly upregulated, with a depolarized half-activation potential and increased maximal current. Although enhanced Ih is typically thought to be associated with decreased dendritic excitability, whole-cell dendritic recordings revealed a robust increase in action potential firing after febrile seizures. We turned to computational simulations to understand how the experimentally observed changes in Ih influence dendritic excitability. Unexpectedly, the simulations, performed in three previously published CA1 pyramidal cell models, showed that the experimentally observed increases in Ih resulted in a general enhancement of dendritic excitability, primarily due to the increased Ih-induced depolarization of the resting membrane potential overcoming the excitability-depressing effects of decreased dendritic input resistance. Taken together, these experimental and modeling results reveal that, contrary to the exclusively anti-convulsive role often attributed to increased Ih in epilepsy, the enhanced Ih can co-exist with, and possibly even contribute to, persistent dendritic hyperexcitability following febrile seizures in the developing hippocampus. HCN Hyperpolarization-Activated Cation Channels Inhibit EPSPs by Interactions with M-type K+ Channels. George MS, Abbott LF, Siegelbaum SA. Nat Neurosci 2009;12(5):577–584. The processing of synaptic potentials by neuronal dendrites depends on both their passive cable properties and active voltage-gated channels, which can generate complex effects as a result of their nonlinear properties. We characterized the actions of HCN (hyperpolarization-activated cyclic nucleotide-gated cation) channels on dendritic processing of subthreshold excitatory postsynaptic potentials (EPSPs) in mouse CA1 hippocampal neurons. The HCN channels generated an excitatory inward current ( Ih) that exerted a direct depolarizing effect on the peak voltage of weak EPSPs, but produced a paradoxical hyperpolarizing effect on the peak voltage of stronger, but still subthreshold, EPSPs. Using a combined modeling and experimental approach, we found that the inhibitory action of Ih was caused by its interaction with the delayed-rectifier M-type K+ current. In this manner, Ih can enhance spike firing in response to an EPSP when spike threshold is low and can inhibit firing when spike threshold is high.

Author(s): Baram, Tallie Z | Abstract: Model of Infantile Spasms Induced by N-methyl-D-aspartic Acid in Prenatally Impaired Brain. Velisek L, Jehle K, Asche S, Veliskova J. Ann Neurol 2007;61(2):109–119. OBJECTIVE: Infantile spasms (a catastrophic epileptic syndrome of childhood) are insensitive to classic antiepileptic drugs. New therapies are limited by lack of animal models. Here we develop a new model of flexion spasms based on prenatal exposure to betamethasone combined with postnatal administration of N-methyl-D-aspartic acid (NMDA) and determine brain structures involved in the induction of flexion spasms. METHODS: Pregnant rats received two doses of betamethasone on day 15 of gestation. Offspring was injected with NMDA on postnatal day 15. Effects of adrenocorticotropin therapy on the development of age-specific flexion spasms were determined and electroencephalographic correlates recorded. C-fos immunohistochemistry and [14C]2-deoxyglucose imaging identified brain structures involved in the development of flexion spasms. RESULTS: Prenatal betamethasone exposure sensitizes rats to development of NMDA-induced spasms and, most importantly, renders the spasms sensitive to adrenocorticotropin therapy. Ictal electroencephalogram results correspond to human infantile spasms: electrodecrement or afterdischarges were observed. Imaging studies defined three principal regions involved in NMDA spasms: limbic areas (except the dorsal hippocampus), hypothalamus, and the brainstem. INTERPRETATION: Despite certain limitations, our new model correlates well with current infantile spasm hypotheses and opens an opportunity for development and testing of new effective drugs.

The human brain is a tremendously complex and still enigmatic three-dimensional structure, composed of countless interconnected neurons and glia. The temporal evolution of the brain throughout life provides a fourth dimension, one that influences every element of the brain's function in health and disease. This temporal evolution contributes to the probability of seizure generation and to the type and the nature of these seizures. The age-specific properties of the brain also influence the consequences of seizures on neuronal structure and behavior. These, in turn, govern epileptic activity and cognitive and emotional functions, contributing to the diverse consequences of seizures and epilepsy throughout life.

Author(s): Noam, Yoav; Baram, Tallie Z | Abstract: Bidirectional Activity-Dependent Regulation of Neuronal Ion Channel Phosphorylation. Misonou H, Menegola M, Mohapatra DP, Guy LK, Park KS, Trimmer JS. J Neurosci 2006;26(52):13505–13514. Activity-dependent dephosphorylation of neuronal Kv2.1 channels yields hyperpolarizing shifts in their voltage-dependent activation and homoeostatic suppression of neuronal excitability. We recently identified 16 phosphorylation sites that modulate Kv2.1 function. Here, we show that in mammalian neurons, compared with other regulated sites, such as serine (S)563, phosphorylation at S603 is supersensitive to calcineurin-mediated dephosphorylation in response to kainate-induced seizures in vivo, and brief glutamate stimulation of cultured hippocampal neurons. In vitro calcineurin digestion shows that supersensitivity of S603 dephosphorylation is an inherent property of Kv2.1. Conversely, suppression of neuronal activity by anesthetic in vivo causes hyperphosphorylation at S603 but not S563. Distinct regulation of individual phosphorylation sites allows for graded and bidirectional homeostatic regulation of Kv2.1 function. S603 phosphorylation represents a sensitive bidirectional biosensor of neuronal activity.