Epilepsia
Glutamate receptor channels mediate transmission at most excitatory synapses throughout the brain, and are thus essential for seizure propagation. Calcium entry through N‐methyl‐d‐aspartate (NMDA) and possibly kainate receptors also triggers many plastic changes that contribute to epileptogenesis. Glutamate receptor structure and function are reviewed in the context of epilepsy. For an expanded treatment...
Group I metabotopic glutamate receptors (mGluRs) can initiate protein synthesis‐dependent intracellular signaling processes that can result in enhanced expression of ictal‐length discharges. Studies reveal that the fragile X syndrome phenotype is mediated by excessive mGluR‐driven protein synthesis. Defective endogenous regulation of mGluR effects may thus enhance patient susceptibility to epileptogenesis...
Seizure discharges involving hippocampus and parahippocampal structures are the hallmark of temporal lobe epilepsy (TLE). Herein we discuss neuronal synchronization in limbic networks from control and epileptic brains under conditions that are inductive for the generation of seizure‐like discharges. In particular, we address the paradoxic role played by inhibitory mechanisms in supporting epileptiform...
Neuronal synchronization occurs when two or more neuronal events are coordinated across time. Local synchronization produces field potentials. Long‐range synchronization between distant brain sites contributes to the electroencephalogram. Neuronal synchronization depends on synaptic (chemical/electrical), ephaptic, and extracellular interactions. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
Hyperpolarization‐activated, cyclic nucleotide‐gated (HCN) channels are voltage‐gated ion channels that influence neuronal excitability in brain regions implicated in both focal and generalized epilepsies. Dysregulation of HCN channel function occurs in many animal models of epilepsy; understanding HCN channel regulation may lead to novel therapies for the prevention and treatment of human epilepsy...
Seizures and epilepsy are fundamentally neuronal circuit phenomena. This article describes the development and application of multiple dynamic imaging techniques that, in combination, facilitate the elucidation of hippocampal circuit function in animal models of epilepsy. This combined approach has significant promise in furthering our understanding of the mechanisms underlying epilepsy. For an expanded...
Some have questioned whether research into basic mechanisms of the epilepsies can have a significant impact on the development of better treatments and cures for patients with epilepsy. In that context, it is helpful to develop clear expectations about what we can accomplish in the laboratory, and how to optimize our contributions. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
Potassium channels are integral to neuronal excitability. They set the resting membrane potential and shape depolarizations caused by excitatory synaptic inputs and action potentials. One potassium channel subgroup—alternatively called the KCNQ, Kv7, or M‐channels—has recently emerged as a viable target for antiepileptic drugs. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
In 1969, H.H. Jasper, A.A. Ward, and A. Pope and the Public Health Service Advisory Committee on the Epilepsies of the National Institutes of Health (NIH) published the first edition on Basic Mechanisms of the Epilepsies (BME). Since then, basic and clinical researchers in epilepsy have gathered together each decade to assess where epilepsy research has been, what it has accomplished, and where it...
Herbert H. Jasper dedicated his life to neuroscience and to epilepsy. He pioneered electroencephalography (EEG) as a tool for studying brain activity in relation to states of consciousness, learning, and epileptic discharge. He also used microelectrodes to record from single neurons and synapses, combined with studies of the underlying neurochemical mechanisms. For an expanded treatment of this topic...
Voltage‐gated Na+ (NaV) channels are key mediators of neuronal function and essential for neuronal excitability. Their abnormal activity is implicated in the generation of seizures, both in acquired and genetic epilepsy. Several of the most widely used antiepileptic drugs inhibit NaV activity by binding to a common receptor site. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
Neural stem cells (NSCs) are one of the candidates for grafting in the realm of cell‐based therapy for temporal lobe epilepsy (TLE). Because NSCs can produce neurons synthesizing the inhibitory neurotransmitter γ‐aminobutyric acid (GABA) and cells secreting multiple neurotrophic factors, NSC grafting therapy has promise for restraining seizures and easing cognitive dysfunction in TLE. For an expanded...
The development of any new therapy for the treatment of a human disorder or disease depends heavily on the demonstration of efficacy in a validated animal model. The need for finding a therapy that would prevent or delay the development of epilepsy in the susceptible individual is evident, and many of the required tools have been developed in recent years. However, there are many practical challenges...
The study of depression as a comorbidity of epilepsy in humans is limited by the attendant iatrogenic and psychosocial variables. In order to study the neurobiology of this clinically important phenomenon without the above‐mentioned confounding factors, we have studied the behavioral and biochemical correlates of epilepsy‐associated depression in two rodent models of limbic epileptogenesis. For an...
Neurosteroids such as allopregnanolone are positive allosteric modulators of γ‐aminobutyric acid (GABA)A receptors with powerful antiseizure activity in diverse animal models. Neurosteroids may be endogenous regulators of seizure susceptibility, for example, in catamenial epilepsy. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of refractory partial seizures and...
Resistance to currently available antiepileptic drugs (AEDs) is a major problem in the treatment of temporal lobe epilepsy that affects approximately 30% of patients. Available evidence suggests that plasticity of AED targets, with a concomitantly decreased sensitivity to AEDs, coexists with other cellular mechanisms to cause drug refractoriness. For an expanded treatment of this topic see Jasper’s basic mechanisms of the epilepsies....
Levetiracetam’s (Keppra) binding site and its subsequent identification as the synaptic vesicle protein 2A (SV2A) enabled the discovery of high affinity SV2A ligands with promising anticonvulsant properties. Among these, brivaracetam was selected for further development. SV2A represents an important antiepileptic drug target validated in both preclinical and clinical studies. For an expanded treatment...
Metabolic changes likely related to the anticonvulsant efficacy of the ketogenic diet include—but are not limited to—ketosis, reduced glucose, elevated fatty acid levels, and enhanced bioenergetic reserves. This review highlights the complex interrelationships between reduced seizures and metabolic adaptations that modulate neuronal excitability and may even afford neuroprotection. For an expanded...
Idiopathic generalized epilepsy (IGE) syndromes are associated with ion channel gene mutations including GABAA receptor subunit gene (GABR) mutations. GABAA receptors are the primary mediators of central nervous system (CNS) inhibitory synaptic transmission, and GABR mutations have been shown to produce GABAergic disinhibition by altering GABAA receptor function and/or impairing receptor biogenesis...
γ‐Aminobutyric acid (GABA)A receptors mediate phasic and tonic inhibition in the brain, and epilepsy‐associated mutations are found in GABAA genes. This chapter discusses a mouse model of human genetic epilepsy and how it has informed our understanding of the role of GABAA receptor dysfunction in patients. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...