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

TLDR

The study investigates how status epilepticus induced by perforant path stimulation in rats leads to hippocampal pathology and long‑term changes relevant to human temporal lobe epilepsy. The authors induced status epilepticus via intermittent perforant path stimulation, replicated the effects with subconvulsive bicuculline, and tested CA1 inhibitory function by contralateral stimulation to probe dormant basket cells. Status epilepticus produced persistent granule cell hyperexcitability, loss of hilar neurons, and reduced GABAergic inhibition, while basket cells remained but lost parvalbumin; contralateral stimulation restored CA1 inhibition, supporting a dormant basket cell hypothesis.

Abstract

Abstract The relationship between an episode of status epilepticus, the resulting hippocampal pathology, and the subsequent development of pathophysiological changes possibly relevant to human cpilepsy 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.