Ictal onset sites and γ‐aminobutyric acidergic neuron loss in epileptic pilocarpine‐treated rats

Abstract

Objective: The present study tested whether ictal onset sites are regions of more severe interneuron loss in epileptic pilocarpine-treated rats, a model of human temporal lobe epilepsy. Methods: Local field potential recordings were evaluated to identify ictal onset sites.Electrode sites were visualized in Nissl-stained sections. Adjacent sections were processed with proximity ligation in situ hybridization for glutamic acid decarboxylase 2 (Gad2). Gad2 neuron profile numbers at ictal onset sites were compared to contralateral regions. Other sections were processed with immunocytochemistry for reelin or nitric oxide synthase (NOS), which labeled major subtypes of granule cell layer-associated interneurons. Stereology was used to estimate numbers of reelin and NOS granule cell layer-associated interneurons per hippocampus. Results: Ictal onset sites varied between and within rats but were mostly in the ventral hippocampus and were frequently bilateral. There was no conclusive evidence of more severe Gad2 neuron profile loss at sites of earliest seizure activity compared to contralateral regions. Numbers of granule cell layer-associated NOS neurons were reduced in the ventral hippocampus. Significance: In epileptic pilocarpine-treated rats, ictal onset sites were mostly in the ventral hippocampus, where there was loss of granule cell layer-associated NOS interneurons. These findings suggest the hypothesis that loss of granule cell layer-associated NOS interneurons in the ventral hippocampus is a mechanism of temporal lobe epilepsy. K E Y W O R D Sepilepsy, focus, hippocampus, interneuron, seizure

Lack of Hyperinhibition of Oriens Lacunosum-Moleculare Cells by Vasoactive Intestinal Peptide-Expressing Cells in a Model of Temporal Lobe Epilepsy

“…VIP+/CR-cells include cholecystokinin-expressing interneurons (Acsady et al, 1996a;Somogyi et al, 2004;Luo et al, 2020) and the loss reported here is consistent with the degeneration of cholecystokinin basket cell boutons, and their reduced collective functional output, in CA1 of epileptic mice (Wyeth et al, 2010;Kang et al, 2021). It is notable that the decrease in VIP+/CR-cell bodies was particularly apparent in temporal hippocampus, a region commonly identified as the seizure onset zone in the pilocarpine model (Toyoda et al, 2013;Wyeth et al, 2020).…”

Optokindling, GABA Dwindling

“…The existence and importance of interneuron excitotoxicity in animal models of epilepsy remain a somewhat unclear picture. 7 - 9 Many such studies rely primarily on the counting of neurons in fixed tissue rather than evaluation of interneuron physiology per se. The approach of Ryu et al enabled in vitro electrophysiological evaluation of interneuron pathology in the epileptic synaptic pathway.…”

Loss of GABAergic Interneurons in Seizure-Induced Epileptogenesis—Two Decades Later and in a More Complex World

“…A more recent study with the pilocarpine model found that ictal onset sites were variable within and between rats, but seizures most frequently occurred in the ventral hippocampus, where interneuron loss was most apparent. 6 Thus, at least so far, it has been difficult to find a definitive role of interneuron loss in these models of acquired epileptogenesis.…”