Neuronal loss induced in limbic pathways by kindling: evidence for induction of hippocampal sclerosis by repeated brief seizures

Abstract

Repeated kindled seizures induce long-lasting physiological and morphological alterations in the hippocampal formation. In the dentate gyrus (DG), the morphological alterations induced by kindled seizures include loss of polymorphic neurons in the hilus, mossy fiber axon sprouting, and synaptic reorganization of the mossy fiber pathway. In this study, quantitative stereological methods were used to determine the distribution and time course of neuronal loss induced by 3, 30, or 150 kindled generalized tonic-clonic seizures in hippocampal, limbic, and neocortical pathways. Neuronal loss was observed in the hilus of the DG and CA1 after three generalized tonic-clonic seizures, and progressed in these sites to 49% and 44% of controls after 150 seizures. Neuronal loss was also observed in CA3, entorhinal cortex, and the rostral endopyriform nucleus after 30 seizures, and was detected in the granule cell layer and CA2 after 150 seizures. There was no evidence of neuronal loss in the somatosensory cortex after 150 seizures. The time course of the neuronal loss demonstrated selective vulnerability of hippocampal neuronal populations to seizure-induced injury, and suggests that even brief seizures may induce excitotoxic injury in vulnerable neuronal populations. Repeated brief seizures induced neuronal loss in a distribution that resembled hippocampal sclerosis, the most common lesion observed in human epilepsy. The results demonstrated that kindling induces alterations in neural circuitry in a variety of locations in the limbic system, and suggest that hippocampal sclerosis may be acquired in human epilepsy as a consequence of repeated seizures.

Chronic Low-Dose Corticosterone Supplementation Enhances Acquired Epileptogenesis in the Rat Amygdala Kindling Model of TLE

“…We cannot exclude the possibility that subtle enhanced neuronal loss in the CS-supplemented rats may have occurred in cell types or brain regions other than the CA1 pyramidal neuron region such as inhibitory interneurons within the hippocampus or neurons in extrahippocampal limbic structures such as the amygdala. However, it is the CA1 pyramidal neurons along with those in CA3 and the dentate hilus that have been shown by previous quantitative stereological studies to be decreased to the greatest extent in rats having undergone amygdala kindling (Cavazos et al, 1994). Importantly, it is these same cell types that are maximally lost in patients with chronic MTLE (Babb and Brown, 1987;Babb et al, 1984).…”

“…Secondly, a quantitative estimation of total neuronal number, density, and region volume was performed for the pyramidal cell layer of the ipsilateral CA1 region of the hippocampus. These cells were chosen for the quantification because previous quantitative stereological studies have shown they, along with those of the CA3 and dentate hilus region, are the cell types that are maximally decreased in rats having undergone amygdala kindling, with neuronal loss being detected after as few as three Class V seizures (Cavazos et al, 1994). Therefore, it would be anticipated that if the CS supplementation resulted in enhanced neuronal cell loss, it would be sensitively detected by quantification of the CA1 pyramidal neurons.…”

Depression Duration But Not Age Predicts Hippocampal Volume Loss in Medically Healthy Women with Recurrent Major Depression

“…Although there has been no direct evidence demonstrating ECT-induced structural brain changes (Devanand et al, 1994), animal electroconvulsive stimulation (ECS) studies suggest that brief kindled seizures may induce selective hippocampal neuronal loss (Cavazos et al, 1994). ECS exposure sufficient to induce kindling, however, far exceeds the human equivalent ECT electrical doses.…”

Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus

“…Keywords choline; kainic acid; hippocampus; seizures; bromodeoxyuridine; growth factor; glutamic acid decarboxylase; glial fibrillary acidic protein; neuroprotection Status epilepticus (SE), a period of prolonged seizures, produces a host of plastic changes in the hippocampus that are thought to contribute to the development of temporal lobe epilepsy. SE results in substantial neuronal loss (Cavazos et al, 1994;Haas et al, 2001;Gorter et al, 2003), γ-aminobutyric acid (GABA) system alterations (e.g., Houser & Esclapez, 1996), reactive gliosis (Jorgensen et al 1993; Niquet et al, 1994a;Kang et al, 2006), mossy fiber innervation of the dentate gyrus (Sutula et al, 1988;Ben-Ari & Represa, 1990), changes in levels of growth factors (Khrestchatisky et al, 1995;Mudo et al, 1996;Schmidt-Kastner et al, 1996;Shetty et al, 2004), and a transient increase in cell proliferation and neurogenesis (Bengzon et al, 1997;Parent et al, 1997;Scharfman et al, 2000;Hattiangady et al, 2004). These SE-induced degenerative and regenerative changes in the hippocampus are also Corresponding author: Dr. Christina L. Williams, Department of Psychology and Neuroscience, 572 Research Drive, Box 91050, GSRB-II, Room 3022, Duke University, Durham, NC 27708, USA, Phone: 919-660-5638, Fax: 919-660-5798, Email: williams@psych.duke.edu.…”

“…SE results in substantial neuronal loss (Cavazos et al, 1994;Haas et al, 2001;Gorter et al, 2003), γ-aminobutyric acid (GABA) system alterations (e.g., Houser & Esclapez, 1996), reactive gliosis (Jorgensen et al 1993;Niquet et al, 1994a;Kang et al, 2006), mossy fiber innervation of the dentate gyrus (Sutula et al, 1988;Ben-Ari & Represa, 1990), changes in levels of growth factors (Khrestchatisky et al, 1995;Mudo et al, 1996;Schmidt-Kastner et al, 1996;Shetty et al, 2004), and a transient increase in cell proliferation and neurogenesis (Bengzon et al, 1997;Parent et al, 1997;Scharfman et al, 2000;Hattiangady et al, 2004). These SE-induced degenerative and regenerative changes in the hippocampus are also accompanied by deficits in hippocampal-dependent learning and memory (Stafstrom et al, 1993;Liu et al, 1994;Sarkisian et al, 1997;Hort et al, 1999;Mikati et al, 2001).…”