Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro

Nov 27, 2002Progress in neurobiology

Brain network and drug factors that cause seizure-like activity in the emotion system in lab studies

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Abstract

Prolonged, NMDA receptor-dependent epileptiform discharges are observed in the entorhinal cortex of control rodents.

These discharges resemble electrographic limbic seizures and propagate to the hippocampus via specific pathways.
GABA receptor-mediated mechanisms paradoxically contribute to the initiation and maintenance of these seizures.
CA3 outputs generate a continuous pattern of interictal discharge at approximately 1Hz, which controls ictal discharge generation.
In the pilocarpine model of epilepsy, this control is weakened, likely due to CA3 cell damage.
Seizure activity spreads to the CA1-subiculum regions through the temporoammonic pathway.
Alterations in network interactions and synaptic plasticity mechanisms may enable the damaged limbic system to produce recurrent seizures.

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Seizures in patients presenting with mesial temporal lobe epilepsy result from the interaction among neuronal networks in limbic structures such as the hippocampus, amygdala and entorhinal cortex. Mesial temporal lobe epilepsy, one of the most common forms of partial epilepsy in adulthood, is generally accompanied by a pattern of brain damage known as mesial temporal sclerosis. Limbic seizures can be mimicked in vitro using preparations of combined hippocampus-entorhinal cortex slices perfused with artificial cerebrospinal fluid containing convulsants or nominally zero Mg(2+), in order to produce epileptiform synchronization. Here, we summarize experimental evidence obtained in such slices from rodents. These data indicate that in control animals: (i) prolonged, NMDA receptor-dependent epileptiform discharges, resembling electrographic limbic seizures, originate in the entorhinal cortex from where they propagate to the hippocampus via the perforant path-dentate gyrus route; (ii) the initiation and maintenance of these ictal discharges is paradoxically contributed by GABA (mainly type A) receptor-mediated mechanisms; and (iii) CA3 outputs, which relay a continuous pattern of interictal discharge at approximately 1Hz, control rather than sustain ictal discharge generation in entorhinal cortex. Recent work indicates that such a control is weakened in the pilocarpine model of epilepsy (presumably as a result of CA3 cell damage). In addition, in these experiments electrographic seizure activity spreads directly to the CA1-subiculum regions through the temporoammonic pathway. Studies reviewed here indicate that these changes in network interactions, along with other mechanisms of synaptic plasticity (e.g. axonal sprouting, decreased activation of interneurons, upregulation of bursting neurons) can confer to the epileptic, damaged limbic system, the ability to produce recurrent limbic seizures as seen in patients with mesial temporal lobe epilepsy.

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Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro

Abstract

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