Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling

Abstract

Seizures in adult rats result in long-term deficits in learning and memory, as well as an enhanced susceptibility to further seizures. In contrast, fewer lasting changes have been found following seizures in rats younger than 20 days old. This age-dependency could be due to differing amounts of hippocampal neuronal damage produced by seizures at different ages. To determine if there is an early developmental resistance to seizure-induced hippocampal damage, we compared the effects of kainic acid (KA)-induced status epilepticus and amygdala kindling on hippocampal dentate gyrus anatomy and electrophysiology, in immature (16 day old) and adult rats. In adult rats, KA status epilepticus resulted in numerous silver-stained degenerating dentate hilar neurons, pyramidal cells in fields CA1 and CA3, and marked numerical reductions in CA3c pyramidal neuron counts (-57%) in separate rats. Two weeks following the last kindled seizure, some, but significantly less, CA3c pyramidal cell loss was observed (-26%). Both KA status epilepticus and kindling in duced mossy-fiber sprouting, as evidenced by ectopic Timm staining in supragranular layers of the dentate gyrus. In hippocampal slices from adult rats, paired-pulse stimulation of perforant path axons revealed a persistent enhancement of dentate granule-cell inhibition following KA status epilepticus or kindling. While seizures induced by KA or kindling in 16-day-old rats were typically more severe than in adults, the immature hippocampus exhibited markedly less KA-induced cell loss (-22%), no kindling-induced loss, no detectable synaptic rearrangement, and no change in dentate inhibition. These results demonstrate that, in immature rats, neither severe KA-induced seizures nor repeated kindled seizures produce the kind of hippocampal damage and changes associated with even less severe seizures in adults. The lesser magnitude of seizure-induced hippocampal alterations in immature rats may explain their greater resistance to long-term effects of seizures on neuronal function, as well as future seizure susceptibility. Conversely, hippocampal neuron loss and altered synaptic physiology in adults may contribute to increased sensitivity to epileptogenic stimuli, spontaneous seizures, and behavioral deficits.

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

“…Enhanced hippocampal plasticity likely plays a significant role in both the memory-enhancing effects of prenatal choline supplementation (Meck & Williams, 2003;McCann et al, 2006) and its neuroprotective actions. Much like our prenatal choline supplemented adult rats, juvenile rats that experience SE also show resistance to seizure-induced hippocampal cell loss, disinhibition, and mossy fiber sprouting (Sperber et al, 1991;Haas et al, 2001), and exhibit savings in spatial learning and memory (Stafstrom et al, 1993;Sarkisian et al, 1997) when compared to adult rats that experience SE. The retention of juvenile-like neuroplasticity and response to seizures into adulthood may contribute to prenatal choline supplementation's preservation of cognitive function in the face of a neural insult.…”

“…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).…”

Effect of age on kainate-induced seizure severity and cell death

“…As a result, the kainate model replicates several phenomenological features of human temporal lobe epilepsy and can be used as an animal preparation to understand the basic mechanisms of epileptogenesis (Ben-Ari, 1985;Turski et al, 1989;Buckmaster and Dudek, 1997). While a large number of studies have addressed age-dependent effects on susceptibility to seizure-induction and seizure-induced cell damage during development (Haas et al, 2001;Baram et al, 2002;Galanopoulou et al, 2002;Lado et al, 2002), few studies have addressed an age-dependent analysis of seizure-induced cell death susceptibility. The present study was aimed at investigating the age-related induction of KAinduced seizure severity in mice and the relation to seizure-induced cell death.…”

Progressive changes in hippocampal cytoarchitecture in a neurodevelopmental rat model of epilepsy: implications for understanding presymptomatic epileptogenesis, predictive diagnosis, and targeted treatments

“…The observation that changes in the hippocampus tend to be region specific may explain the many conflicting reports on hippocampal alterations following excitatory intervention, particularly in the neonate. Some authors report longterm hippocampal changes following neonatal excitotoxicity [44][45][46][47][48][49], while others report that the hippocampus is relatively resistant to these changes [28,[50][51][52][53][54]. It is possible that some of these discrepancies result from methodological differences whereby only select regions of the hippocampus were examined.…”