Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: The “dormant basket cell” hypothesis and its possible relevance to temporal lobe epilepsy

Jan 1, 1991Hippocampus

Lasting changes in hippocampus structure and nerve cell activity after severe seizures in rats: the 'silent inhibitory cell' idea and its possible link to temporal lobe epilepsy

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Abstract

Granule cell hyperexcitability and decreased inhibition were observed after 24 hours of stimulation, persisting for over 1 year.

Pathophysiological changes in granule cells may be linked to reduced GABA-mediated inhibition.
Loss of dentate hilar mossy cells and specific inhibitory neurons correlates with granule cell hyperexcitability.
Surviving GABA-immunoreactive dentate basket cells show a lack of parvalbumin on the stimulated side.
CA1 pyramidal cells display hyperexcitability despite minimal damage to their structure.
Contralateral stimulation can restore paired-pulse inhibition in CA1 pyramidal cells, suggesting that inhibitory systems in 'epileptic' tissue can function if activated.

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The relationship between an episode of status epilepticus, the resulting hippocampal pathology, and the subsequent development of pathophysiological changes possibly relevant to human epilepsy was explored using the experimental epilepsy model of perforant path stimulation in the rat. Granule cell hyperexcitability and decreased feedforward and feedback inhibition were evident immediately after 24 hours of intermittent perforant path stimulation and persisted relatively unchanged for more than 1 year. All of the pathophysiological changes induced by perforant path stimulation were replicated in normal animals by a subconvulsive dose of bicuculline, suggesting that the permanent "epileptiform" abnormalities produced by sustained perforant path stimulation may be due to decreased GABA-mediated inhibition. Granule cell pathophysiology was seen only in animals that exhibited a loss of adjacent dentate hilar mossy cells and hilar somatostatin/neuropeptide Y-immunoreactive neurons. GABA-immunoreactive dentate basket cells survived despite the extensive loss of adjacent hilar neurons. However, parvalbumin immunoreactivity, present normally in a subpopulation of GABA-immunoreactive dentate basket cells, was absent on the stimulated side. Whether this represents decreased parvalbumin synthesis in surviving basket cells or a loss of a specific subset of inhibitory cells is unclear. Hyperexcitability and decreased paired-pulse inhibition in response to ipsilateral perforant path stimulation were also present in the CA1 pyramidal cell layer on the previously stimulated side, despite minimal damage to CA1 pyramidal cells or interneurons. The possibility that CA1 inhibitory neurons were hypofunctional or "dormant" due to a loss of excitatory input to inhibitory cells from damaged CA3 pyramidal cells was tested by stimulating the contralateral perforant path in order to activate the same CA1 basket cells via different inputs. Contralateral stimulation evoked CA1 pyramidal cell paired-pulse inhibition immediately in the previously stimulated hippocampus. Thus, we propose the "dormant basket cell" hypothesis, which implies that despite malfunction, inhibitory systems remain intact in "epileptic" tissue and are capable of functioning if appropriately activated.

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Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: The “dormant basket cell” hypothesis and its possible relevance to temporal lobe epilepsy

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