Targeted hippocampal GABA neuron ablation by Stable Substance P-saporin causes hippocampal sclerosis and chronic epilepsy in rats.

Cryptogenic temporal lobe epilepsy develops in the absence of identified brain injuries, infections, or structural malformations, and in these cases, an unidentified pre-existing abnormality may initiate febrile seizures, hippocampal sclerosis, and epilepsy. Although a role for GABAergic dysfunction in epilepsy is intuitively obvious, no causal relationship has been established. In this study, hippocampal GABA neurons were targeted for selective elimination to determine whether a focal hippocampal GABAergic defect in an otherwise normal brain can initiate cryptogenic temporal lobe epilepsy with hippocampal sclerosis.

No latency to dentate granule cell epileptogenesis in experimental temporal lobe epilepsy with hippocampal sclerosis.

Objective: To determine when spontaneous granule cell epileptiform discharges first occur after hippocampal injury, and to identify the postinjury "latent" period as either a "silent" gestational state of epileptogenesis or a subtle epileptic state in gradual transition to a more obvious epileptic state.

Methods: Nonconvulsive status epilepticus evoked by perforant path stimulation in urethane-sedated rats produced selective and extensive hippocampal injury and a "latent" period that preceded the onset of the first clinically obvious epileptic seizures. Continuous granule cell layer depth recording and video monitoring assessed the time course of granule cell hyperexcitability and the onset/offset times of spontaneous epileptiform discharges and behavioral seizures.

Epileptic pilocarpine-treated rats exhibit aberrant hippocampal EPSP-spike potentiation but retain long-term potentiation.

Hippocampal neuron plasticity is strongly associated with learning, memory, and cognition. In addition to modification of synaptic function and connectivity, the capacity of hippocampal neurons to undergo plasticity involves the ability to change nonsynaptic excitability. This includes altering the probability that EPSPs will generate action potentials (E-S plasticity).

Epileptogenesis meets Occam's Razor.

Pharmacological treatment to prevent brain injury-induced temporal lobe epileptogenesis has been generally unsuccessful, raising the issues of exactly when the conversion process to an epileptic brain state occurs and reaches completion, and which cellular or network processes might be the most promising therapeutic targets. The time course of epileptogenesis is a central issue, with recent results suggesting that injury-induced epileptogenesis can be a much more rapid process than previously thought, and may be inconsistent with a delayed epileptogenic mechanism. Simplification of the seemingly complex issues involved in the use of epilepsy animal models might lead to a better understanding of the nature of injury-induced epileptogenesis, the significance of the 'latent' period, and whether current strategies should focus on preventing or modifying epilepsy.

Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models.

Global expression profiling of neurologic or psychiatric disorders has been confounded by variability among laboratories, animal models, tissues sampled, and experimental platforms, with the result being that few genes demonstrate consistent expression changes. We attempted to minimize these confounds by pooling dentate granule cell transcriptional profiles from 164 rats in seven laboratories, using three status epilepticus (SE) epilepsy models (pilocarpine, kainate, self-sustained SE), plus amygdala kindling. In each epilepsy model, RNA was harvested from laser-captured dentate granule cells from six rats at four time points early in the process of developing epilepsy, and data were collected from two independent laboratories in each rodent model except SSSE.

Standardized environmental enrichment supports enhanced brain plasticity in healthy rats and prevents cognitive impairment in epileptic rats.

Environmental enrichment of laboratory animals influences brain plasticity, stimulates neurogenesis, increases neurotrophic factor expression, and protects against the effects of brain insult. However, these positive effects are not constantly observed, probably because standardized procedures of environmental enrichment are lacking. Therefore, we engineered an enriched cage (the Marlau™ cage), which offers: (1) minimally stressful social interactions; (2) increased voluntary exercise; (3) multiple entertaining activities; (4) cognitive stimulation (maze exploration), and (5) novelty (maze configuration changed three times a week).

Updating the lamellar hypothesis of hippocampal organization.

Andersen et al. (1971) proposed that excitatory activity in the entorhinal cortex propagates topographically to the dentate gyrus, and on through a "trisynaptic circuit" lying within transverse hippocampal "slices" or "lamellae." In this way, a relatively simple structure might mediate complex functions in a manner analogous to the way independent piano keys can produce a nearly infinite variety of unique outputs.

Defining "epileptogenesis" and identifying "antiepileptogenic targets" in animal models of acquired temporal lobe epilepsy is not as simple as it might seem.

The "latent period" between brain injury and clinical epilepsy is widely regarded to be a seizure-free, pre-epileptic state during which a time-consuming cascade of molecular events and structural changes gradually mediates the process of "epileptogenesis." The concept of the "latent period" as the duration of "epileptogenesis" implies that epilepsy is not an immediate result of brain injury, and that anti-epileptogenic strategies need to target delayed secondary mechanisms that develop sometime after an initial injury. However, depth recordings made directly from the dentate granule cell layers in awake rats after convulsive status epilepticus-induced injury have now shown that whenever perforant pathway stimulation-induced status epilepticus produces extensive hilar neuron loss and entorhinal cortical injury, hyperexcitable granule cells immediately generate spontaneous epileptiform discharges and focal or generalized behavioral seizures.

Electrical stimulation-induced seizures in rats: a "dose-response" study on resultant neurodegeneration.

Perforant pathway stimulation (PPS) is used to study temporal lobe epilepsy in rodents. High-frequency PPS induces acute seizures, which can lead to neuron death and spontaneous epilepsy. However, the minimum duration of PPS that induces neurodegeneration in naive rodents is unknown.

Classic hippocampal sclerosis and hippocampal-onset epilepsy produced by a single "cryptic" episode of focal hippocampal excitation in awake rats.

In refractory temporal lobe epilepsy, seizures often arise from a shrunken hippocampus exhibiting a pattern of selective neuron loss called "classic hippocampal sclerosis." No single experimental injury has reproduced this specific pathology, suggesting that hippocampal atrophy might be a progressive "endstage" pathology resulting from years of spontaneous seizures. We posed the alternative hypothesis that classic hippocampal sclerosis results from a single excitatory event that has never been successfully modeled experimentally because convulsive status epilepticus, the insult most commonly used to produce epileptogenic brain injury, is too severe and necessarily terminated before the hippocampus receives the needed duration of excitation.

Hippocampal injury, atrophy, synaptic reorganization, and epileptogenesis after perforant pathway stimulation-induced status epilepticus in the mouse.

Prolonged dentate granule cell discharges produce hippocampal injury and chronic epilepsy in rats. In preparing to study this epileptogenic process in genetically altered mice, we determined whether the background strain used to generate most genetically altered mice, the C57BL/6 mouse, is vulnerable to stimulation-induced seizure-induced injury. This was necessary because C57BL/6 mice are reportedly resistant to the neurotoxic effects of kainate-induced seizures, which we hypothesized to be related to strain differences in kainate's effects, rather than genetic differences in intrinsic neuronal vulnerability.

Hippocampal epileptogenesis in animal models of mesial temporal lobe epilepsy with hippocampal sclerosis: the importance of the "latent period" and other concepts.

Prolonged chemoconvulsant-induced status epilepticus in rats has long been promoted as an animal model of mesial temporal lobe epilepsy with hippocampal sclerosis, under the assumption that these animals involve: (1) pathology similar to that of the human neurologic condition; (2) a seizure-free, "preepileptic" latent period of several weeks duration after injury, during which a secondary epileptogenic process gradually develops; and (3) a chronic epileptic state in which the hippocampus, in general, and the dentate gyrus, in particular, becomes a source of the spontaneous behavioral seizures that define these animals as "epileptic." Retrospective analysis suggests that all of these assumptions are in doubt. Neuropathologic studies have shown that prolonged status epilepticus causes greater extrahippocampal than hippocampal damage, and does not produce classic hippocampal sclerosis.

Minimal latency to hippocampal epileptogenesis and clinical epilepsy after perforant pathway stimulation-induced status epilepticus in awake rats.

Hippocampal epileptogenesis is hypothesized to involve secondary mechanisms triggered by initial brain injury. Chemoconvulsant-induced status epilepticus has been used to identify secondary epileptogenic mechanisms under the assumption that a seizure-free, preepileptic "latent period" exists that is long enough to accommodate delayed mechanisms. The latent period is difficult to assess experimentally because early spontaneous seizures may be caused or influenced by residual chemoconvulsant that masks the true duration of the epileptogenic process.

Synapses formed by normal and abnormal hippocampal mossy fibers.

The axon terminals (mossy fibers) of hippocampal dentate granule cells form characteristic synaptic connections with large spines or excrescences of both hilar mossy cells and CA3 pyramidal neurons. Interneurons of the hilar region and area CA3 are also prominent targets of mossy fibers. The tracing of biocytin-filled mossy fibers and immunolabeling of target cells with interneuron markers has revealed that the majority of mossy fiber synapses project to gamma aminobutyric acid (GABA)-ergic inhibitory interneurons rather than to excitatory principal cells, although the functional implications of these quantitative differences are unclear.

Neuronal hyperactivity induces astrocytic expression of neurocan in the adult rat hippocampus.

Extracellular matrix molecules are involved in the cellular functions of proliferation, migration, morphological differentiation, and synaptic plasticity. One candidate molecule of the extracellular matrix is the chondroitin sulfate proteoglycan neurocan. To determine whether neurocan expression is regulated by neuronal activity in the adult rat brain, we studied changes in hippocampal neurocan mRNA and protein expression following electrical stimulation of the perforant pathway in urethane-anesthetized rats.

Kainic acid-induced recurrent mossy fiber innervation of dentate gyrus inhibitory interneurons: possible anatomical substrate of granule cell hyper-inhibition in chronically epileptic rats.

Kainic acid-induced neuron loss in the hippocampal dentate gyrus may cause epileptogenic hyperexcitability by triggering the formation of recurrent excitatory connections among normally unconnected granule cells. We tested this hypothesis by assessing granule cell excitability repeatedly within the same awake rats at different stages of the synaptic reorganization process initiated by kainate-induced status epilepticus (SE). Granule cells were maximally hyperexcitable to afferent stimulation immediately after SE and became gradually less excitable during the first month post-SE.

Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.

Aggregation of the amyloid-beta (Abeta) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Abeta aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours.

Hippocampal granule cell activity and c-Fos expression during spontaneous seizures in awake, chronically epileptic, pilocarpine-treated rats: implications for hippocampal epileptogenesis.

The process of postinjury hippocampal epileptogenesis may involve gradually developing dentate granule cell hyperexcitability caused by neuron loss and synaptic reorganization. We tested this hypothesis by repeatedly assessing granule cell excitability after pilocarpine-induced status epilepticus (SE) and monitoring granule cell behavior during 235 spontaneous seizures in awake, chronically implanted rats. During the first week post-SE, granule cells exhibited diminished paired-pulse suppression and decreased seizure discharge thresholds in response to afferent stimulation.

The neurobiology of temporal lobe epilepsy: too much information, not enough knowledge.

Although there are many types of epilepsy of both genetic and acquired forms, temporal lobe epilepsy (TLE) with hippocampal sclerosis is probably the single most common human epilepsy, and the one most intensely studied. Despite a wealth of descriptive data obtained from patient histories, imaging techniques, electroencephalographic recording, and histological studies, the epileptogenic process remains poorly understood. Progress toward understanding the etiology of an acquired neurological disorder is largely dependent on the degree to which experimental animal models reflect the human condition.