Decreased Hippocampal Inhibition and a Selective Loss of Interneurons in Experimental Epilepsy

TLDR

Seizure activity in temporal lobe epilepsy is linked to characteristic hippocampal cell loss. The study developed an electrical stimulation model of hippocampal afferent pathways to replicate seizure‑induced cell loss and examine resulting structural and functional changes. Repetitive electrical stimulation of the hippocampal afferent pathway was used to induce seizures and mimic the hippocampal damage seen in human epilepsy. Seizure activity caused persistent loss of recurrent inhibition and irreversible damage to adjacent interneurons, with somatostatin‑containing interneurons and mossy cells nearly completely lost while GABAergic neurons survived, indicating that loss of the basket‑cell‑activating system drives disinhibition in epilepsy.

Abstract

The occurrence of seizure activity in human temporal lobe epilepsy or status epilepticus is often associated with a characteristic pattern of cell loss in the hippocampus. An experimental model that replicates this pattern of damage in normal animals by electrical stimulation of the afferent pathway to the hippocampus was developed to study changes in structure and function that occur as a result of repetitive seizures. Hippocampal granule cell seizure activity caused a persistent loss of recurrent inhibition and irreversibly damaged adjacent interneurons. Immunocytochemical staining revealed unexpectedly that γ-aminobutyric acid (GABA)-containing neurons, thought to mediate inhibition in this region and predicted to be damaged by seizures, had survived. In contrast, there was a nearly complete loss of adjacent somatostatin-containing interneurons and mossy cells that may normally activate inhibitory neurons. These results suggest that the seizure-induced loss of a basket cell-activating system, rather than a loss of inhibitory basket cells themselves, may cause disinhibition and thereby play a role in the pathophysiology and pathology of the epileptic state.