Dexamethasone Attenuates Hyperexcitability Provoked by Experimental Febrile Status Epilepticus.

The role of neuroinflammation in the mechanisms of epilepsy development is important because inflammatory mediators provide tractable targets for intervention. Inflammation is intrinsically involved in the generation of childhood febrile seizures (FSs), and prolonged FS [febrile status epilepticus (FSE)] precedes a large proportion of adult cases of temporal lobe epilepsy (TLE). As TLE is often refractory to therapy and is associated with serious cognitive and emotional problems, we investigated whether its development can be prevented using anti-inflammatory strategies.

Epilepsy-predictive magnetic resonance imaging changes following experimental febrile status epilepticus: Are they translatable to the clinic?

Objective: A subset of children with febrile status epilepticus (FSE) are at risk for development of temporal lobe epilepsy later in life. We sought a noninvasive predictive marker of those at risk that can be identified soon after FSE, within a clinically realistic timeframe.

Methods: Longitudinal T -weighted magnetic resonance imaging (T WI MRI) of rat pups at several time points after experimental FSE (eFSE) was performed on a high-field scanner followed by long-term continuous electroencephalography.

Dual and Opposing Roles of MicroRNA-124 in Epilepsy Are Mediated through Inflammatory and NRSF-Dependent Gene Networks.

Insult-provoked transformation of neuronal networks into epileptic ones involves multiple mechanisms. Intervention studies have identified both dysregulated inflammatory pathways and NRSF-mediated repression of crucial neuronal genes as contributors to epileptogenesis. However, it remains unclear how epilepsy-provoking insults (e.

Hyper-excitability and epilepsy generated by chronic early-life stress.

Epilepsy is more prevalent in populations with high measures of stress, but the neurobiological mechanisms are unclear. Stress is a common precipitant of seizures in individuals with epilepsy, and may provoke seizures by several mechanisms including changes in neurotransmitter and hormone levels within the brain. Importantly, stress during sensitive periods early in life contributes to 'brain programming', influencing neuronal function and brain networks.

A novel, noninvasive, predictive epilepsy biomarker with clinical potential.

A significant proportion of temporal lobe epilepsy (TLE), a common, intractable brain disorder, arises in children with febrile status epilepticus (FSE). Preventative therapy development is hampered by our inability to identify early the FSE individuals who will develop TLE. In a naturalistic rat model of FSE, we used high-magnetic-field MRI and long-term video EEG to seek clinically relevant noninvasive markers of epileptogenesis and found that reduced amygdala T2 relaxation times in high-magnetic-field MRI hours after FSE predicted experimental TLE.

Inflammatory processes, febrile seizures, and subsequent epileptogenesis.

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.

Epileptogenesis after prolonged febrile seizures: mechanisms, biomarkers and therapeutic opportunities.

Epidemiological and recent prospective analyses of long febrile seizures (FS) and febrile status epilepticus (FSE) support the idea that in some children, such seizures can provoke temporal lobe epilepsy (TLE). Because of the high prevalence of these seizures, if epilepsy was to arise as their direct consequence, this would constitute a significant clinical problem. Here we discuss these issues, and describe the use of animal models of prolonged FS and of FSE to address the following questions: Are long FS epileptogenic? What governs this epileptogenesis? What are the mechanisms? Are there any predictive biomarkers of the epileptogenic process, and can these be utilized, together with information about the mechanisms of epileptogenesis, for eventual prevention of the TLE that results from long FS and FSE.

Temperature elevation increases GABA(A) -mediated cortical inhibition in a mouse model of genetic epilepsy.

A missense mutation (R43Q) in the γ2 subunit of the γ-aminobutyric acid (GABA)(A) receptor is associated with generalized (genetic) epilepsy with febrile seizures plus (GEFS+). Heterozygous GABA(A) γ2(R43Q) mice displayed a lower temperature threshold for thermal seizures as compared to wild-type littermates. Temperature-dependent internalization of GABA(A) γ2(R43Q)-containing receptors has been proposed as a mechanism underlying febrile seizure genesis in patients with this mutation.

Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling.

Stress affects the hippocampus, a brain region crucial for memory. In rodents, acute stress may reduce density of dendritic spines, the location of postsynaptic elements of excitatory synapses, and impair long-term potentiation and memory. Steroid stress hormones and neurotransmitters have been implicated in the underlying mechanisms, but the role of corticotropin-releasing hormone (CRH), a hypothalamic hormone also released during stress within hippocampus, has not been elucidated.

Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers.

Whether long febrile seizures (FSs) can cause epilepsy in the absence of genetic or acquired predisposing factors is unclear. Having established causality between long FSs and limbic epilepsy in an animal model, we studied here if the duration of the inciting FSs influenced the probability of developing subsequent epilepsy and the severity of the spontaneous seizures. We evaluated if interictal epileptifom activity and/or elevation of hippocampal T2 signal on magnetic resonance image (MRI) provided predictive biomarkers for epileptogenesis, and if the inflammatory mediator interleukin-1beta (IL-1beta), an intrinsic element of FS generation, contributed also to subsequent epileptogenesis.

Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities.

Voltage-gated sodium channels are required for the initiation and propagation of action potentials. Mutations in the neuronal voltage-gated sodium channel SCN1A are associated with a growing number of disorders including generalized epilepsy with febrile seizures plus (GEFS+),(7) severe myoclonic epilepsy of infancy, and familial hemiplegic migraine. To gain insight into the effect of SCN1A mutations on neuronal excitability, we introduced the human GEFS+ mutation SCN1A-R1648H into the orthologous mouse gene.

Mice lacking doublecortin and doublecortin-like kinase 2 display altered hippocampal neuronal maturation and spontaneous seizures.

Mutations in doublecortin (DCX) are associated with intractable epilepsy in humans, due to a severe disorganization of the neocortex and hippocampus known as classical lissencephaly. However, the basis of the epilepsy in lissencephaly remains unclear. To address potential functional redundancy with murin Dcx, we targeted one of the closest homologues, doublecortin-like kinase 2 (Dclk2).

Febrile seizures: mechanisms and relationship to epilepsy.

Studies of febrile seizures have been driven by two major enigmas: first, how these most common of human seizures are generated by fever has not been known. Second, epidemiological studies have linked prolonged febrile seizures with the development of temporal lobe epilepsy, yet whether long or recurrent febrile seizures cause temporal lobe epilepsy has remained unresolved. To investigate these questions, a model of prolonged (complex) febrile seizures was developed in immature rats and mice, permitting mechanistic examination of the potential causal relationships of fever and seizures, and of febrile seizures and limbic epilepsy.

Cognitive dysfunction after experimental febrile seizures.

While the majority of children with febrile seizures have an excellent prognosis, a small percentage are later discovered to have cognitive impairment. Whether the febrile seizures produce the cognitive deficits or the febrile seizures are a marker or the result of underlying brain pathology is not clear from the clinical literature. We evaluated hippocampal and prefrontal cortex function in adult rats with a prior history of experimental febrile seizures as rat pups.

Rapid loss of dendritic spines after stress involves derangement of spine dynamics by corticotropin-releasing hormone.

Chronic stress causes dendritic regression and loss of dendritic spines in hippocampal neurons that is accompanied by deficits in synaptic plasticity and memory. However, the responsible mechanisms remain unresolved. Here, we found that within hours of the onset of stress, the density of dendritic spines declined in vulnerable dendritic domains.

Fever, febrile seizures and epilepsy.

Seizures induced by fever (febrile seizures) are the most common type of pathological brain activity in infants and children. These febrile seizures and their potential contribution to the mechanisms of limbic (temporal lobe) epilepsy have been a topic of major clinical and scientific interest. Key questions include the mechanisms by which fever generates seizures, the effects of long febrile seizures on neuronal function and the potential contribution of these seizures to epilepsy.