Multiple Kainic Acid Seizures in the Immature and Adult Brain: Ictal Manifestations and Long–Term Effects on Learning and Memory

Abstract

Summary:Purpose: While there is increasing evidence that the adverse effects of prolonged seizures are less pronounced in the immature than in the mature brain, there have been few investigations of the long-term effects of recurrent seizures during development. This study examined the effects of multiple administrations of the convulsant kainic acid (KA) on seizure characteristics and spatial learning as a function of brain development.Metho& To determine the long-term effects of serial KA seizures during ontogeny, saline or convulsant doses of KA were given intraperitoneally 4 times, at 2-day intervals. Immature rats were given KA on P20, P22, P24 and P26; adult rats got KA on P60, P62, P64 and P66. Ictal characteristics and EEGs were recorded. To examine the effects of multiple KA seizures on the retention of spatial learning, water maze testing was performed before (immature group: from P16-19, adult group: from P56-P59) and after (immature: from P60-P63, adult: from PIOO-Pl03) KA injections. Finally, histology was performed to compare KA-induced damage at each age.Results: In immature animals, serial KA administration resulted in seizures with a progressively longer onset latency and decreased severity. In contrast, KA serially administered to adult rats caused severe seizures after each of the 4 injections.In immature rats, epileptiform EEG changes were most prominent after the first KA injection, whereas in adults, prolonged paroxysmal EEG patterns were seen after all 4 KA injections. Before KA, both rat pups and adults acquired place learning in the water maze. One month after the final KA injection, there was no deficit in spatial learning retention in the immature group, whereas the adult group had profound impairment compared to age-matched, saline-injected controls. Histology revealed no lesions in immature rats treated multiple times with KA but profound cell loss in hippocampal fields CA4, CA3 and CAI in rats treated serially with KA as adults.Conclusions: Previous studies have shown that a single KA injection causes prolonged status epilepticus (which persists for several hours), leading to severe histologic and behavioral sequelae in adult rats but not in pups. Our study extends those findings, demonstrating that immature rats are spared the cognitive and pathological sequelae of multiple injections of convulsant doses of KA as well.

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.…”

“…Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 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). Understanding the relationship between the hippocampal response to SE and its cognitive consequences may lead to new insights into the treatment of SE and 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 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). Understanding the relationship between the hippocampal response to SE and its cognitive consequences may lead to new insights into the treatment of SE and epilepsy.…”

Zinc transporter 3 is involved in learned fear and extinction, but not in innate fear

“…Is it possible that possible susceptibility to seizures leads to memory deficits in ZnT3 KO mice? Zinc deficiency is known to sensitize animals to seizure induction (Takeda et al 2003(Takeda et al , 2006 and it is also known that seizures disrupt consolidation processes (Moore et al 1993;Sarkisian et al 1997). While we cannot exclude the possibility that subseizures might occur in the mutant animals, we have never observed seizures in ZnT3 KO mice in the home cage or during any of our behavioral procedures involving electric shock in fear conditioning and testing for electric shock sensitivity.…”

Epileptogenesis Is Increased in Rats With Neonatal Isolation and Early-Life Seizure and Ameliorated by MK-801: A Long-Term MRI and Histological Study

“…Animal studies have demonstrated that early-life seizures differ essentially from seizures in the adult, including the seizure behaviors, the EEG features, and their consequences. Notwithstanding the higher susceptibility to seizures, the immature brain is less vulnerable to seizure-induced injuries than the mature brain (1)(2)(3)(4)(5), and diverse conditions, such as the seizure severity, causes of seizure, or precipitating injuries may affect the long-term neurologic outcome (6 -9). In this regard, the circumstances under which a seizure in immature brain can cause permanent brain damage is of great interest (9,10).…”