Review
The kainic acid model of temporal lobe epilepsy

https://doi.org/10.1016/j.neubiorev.2013.10.011Get rights and content

Highlights

  • The kainic acid model is a reliable tool to study temporal lobe epilepsy.

  • Differences exist between intracerebral and systemic administrations.

  • Differences exist between the kainic acid, the pilocarpine and the kindling model.

  • Species and age specificity characterize the kainic acid model.

  • These differences should be considered when using the kainic acid model.

Abstract

The kainic acid model of temporal lobe epilepsy has greatly contributed to the understanding of the molecular, cellular and pharmacological mechanisms underlying epileptogenesis and ictogenesis. This model presents with neuropathological and electroencephalographic features that are seen in patients with temporal lobe epilepsy. It is also characterized by a latent period that follows the initial precipitating injury (i.e., status epilepticus) until the appearance of recurrent seizures, as observed in the human condition. Finally, the kainic acid model can be reproduced in a variety of species using either systemic, intrahippocampal or intra-amygdaloid administrations. In this review, we describe the various methodological procedures and evaluate their differences with respect to the behavioral, electroencephalographic and neuropathological correlates. In addition, we compare the kainic acid model with other animal models of temporal lobe epilepsy such as the pilocarpine and the kindling model. We conclude that the kainic acid model is a reliable tool for understanding temporal lobe epilepsy, provided that the differences existing between methodological procedures are taken into account.

Introduction

According to the World Health Organization, epilepsy is the most prevalent neurological disorder, with a prevalence of over 50 million and an incidence of 2.4 million per year. Partial epileptic disorders represent 60% of these cases, with temporal lobe epilepsy (TLE) being the most common type. Symptoms in TLE consist of partial seizures that originate from the hippocampus, entorhinal cortex or amygdala many years after an initial brain insult such as status epilepticus (SE), encephalitis or febrile convulsions. Many antiepileptic drugs are currently available to control or to reduce seizure occurrence, but approximately one third of patients are refractory to medication, making TLE one of the most refractory form of partial epilepsy in adults (Engel et al., 2012). In such patients, surgical resection of the epileptic tissue remains the only therapeutic alternative. However, the seizure onset zone and possible post-surgical neurological deficits must be assessed with multiple and costly tests including pre-surgical invasive procedures such as intracranial EEG recordings.

Patients with TLE typically show hippocampal sclerosis, characterized by selective neuronal loss in the CA1/CA3 region of the hippocampus and the hilus, along with granule cell dispersion and aberrant mossy fiber sprouting in the molecular layer of the dentate gyrus (Berkovic et al., 1991, Buckmaster, 2012, Gloor, 1997, Jackson et al., 1990, Thorn, 1997). Removing the sclerotic hippocampus will reduce seizure occurrence but still approximately 30% of patients are not seizure-free after surgery because of insufficient resection of the epileptic tissue. Indeed, it was hypothesized that TLE may involve a broad extrahippocampal, or even extratemporal, network (Bartolomei et al., 2008, Harroud et al., 2012, Najm et al., 2013, Spencer, 2002, Spencer and Spencer, 1994) since performing a total resection of the hippocampus is more effective in controlling seizures compared to a lobectomy restricted to only the anterior part of the temporal lobe (Wyler et al., 1995). Finally, in some patients, the seizure onset zone cannot be clearly identified and thus they become poor candidates for surgical treatment.

Taken together, these clinical findings put further emphasis on the need to use experimental models of TLE to replicate the histopathological, electroencephalographic and behavioral features encountered in this neurological disorder in order to answer many unresolved questions; these include the localization and extent of the seizure onset zone as well as the mechanisms underlying epileptogenesis. The identification of the seizure onset zone is especially important for the surgical treatment of TLE while understanding epileptogenesis is crucial for establishing the evolution of this epileptic disorder since “seizures may beget seizures”, by inducing additional neuronal damage or aberrant synaptogenesis (Ben-Ari et al., 2008).

Although there is no experimental model that reproduces all the features of TLE, some models have been extensively used over the past decades because of their high level of similarity with human epilepsy. One of these is the kainic acid (KA) model, that was originally discovered by Ben-Ari (Ben-Ari and Lagowska, 1978, Ben-Ari et al., 1979a). In these initial studies, they showed that intra-amydaloid injections of KA induce behavioral seizures and produce neuropathological lesions that are similar to those occurring in patients with TLE (i.e., neuronal degeneration in the CA3 region of the dorsal hippocampus).

In this paper, we will review the results obtained from in vivo studies in which KA was administered intracerebrally or systemically. For each method, we will summarize their associated behavioral, electroencephalographic and neuropathological features. In addition, we will compare the epileptogenic properties of KA following intracerebral or systemic injection as well as the influence of the age of the animals on both KA-induced seizures and associated neuropathological changes. Finally, we will compare the KA model to two other models of TLE, namely the pilocarpine model and the kindling model.

Section snippets

Kainic acid

KA is a cyclic analog of l-glutamate and an agonist of ionotropic KA receptors. It was isolated and extracted in the early 1950s, from a red algae (Digenea simplex) found in tropical and sub-tropical waters (Murakami et al., 1953). It was named digenic acid but this term was later changed to KA in order to avoid confusion with the other derivatives of Digenea (Nadler, 1979). KA was first meant to be used as an ascaricide to eradicate ascariasis, a disease caused by the parasitic worm Ascaris

Intracerebral administration of KA

One of the first studies showing an effect of KA on hippocampal neurons was published by Nadler et al. (1978). These experiments demonstrated that intraventricular injections of KA (0.5 nmol) in Sprague–Dawley rats caused one to three days after treatment pyramidal cell degeneration in CA3 at the rostral pole of the hippocampus whereas higher doses (0.8 μg) induced neuronal loss in more caudal regions of the hippocampus. Doses that were higher than 0.8 μg induced neurodegeneration in CA1 and CA2.

Behavioral manifestations

The main advantage of using systemic administrations of KA compared to intracerebral administrations are that many animals can be injected at one time and it does not require from the experimenter to perform surgical procedures, which therefore eliminates post-surgical complications that could affect the animal's health or damage to the brain tissue made by the cannula. However, its main disadvantages are that one has no control on the bio-availability of KA in the brain and some animals may

Age specificity

It is known that brains in young animals are hyperexcitable when compared to adults. For instance, Holmes and Thompson (1988) showed that young rats (P12) exhibit more severe SE following intraperitoneal injection of KA compared to adult animals (P27). This difference could not be explained by the degree of damage induced by SE since no histological lesions were found in the two groups. Moreover, animals in both groups developed spontaneous seizures. Stafstrom et al. (1992) have also reported

The pilocarpine model

The electroencephalographic features and the neuropathological alterations seen in pilocarpine-treated animals are similar to what is reported with KA. Following pilocarpine intrahippocampal administration, the first epileptiform discharge occurs in the hippocampus and there is mossy fiber sprouting in the inner molecular layer of the dentate gyrus (Furtado et al., 2002). With systemic administration of pilocarpine, more extensive lesions are observed since there are morphological changes in

Conclusive remarks

After three decades of active epilepsy research, the KA model is still one of the most widely used animal models of TLE. It has allowed investigators to study ictogenesis and epileptogenesis from single neurons to networks, and results obtained do support the hypothesis that epilepsy results from a complex interaction between aberrant network activity and morphological changes. In this paper, we have reviewed evidence supporting the view that the KA model is a highly isomorphic model of the

Conflicts of interest

None of the authors has any conflict of interest to disclose.

Acknowledgments

This review was supported by the Canadian Institutes of Health Research (CIHR grants 8109 and 74609). ML was recipient of a post-doctoral fellowship from the Savoy Foundation. We thank Dr Lionel Carmant, Dr J Victor Nadler, Dr Karen Moxon and Ms Suganya Karunakaran for providing the EEG recordings and histological samples shown in this review. We also thank Dr. Philippe Séguéla for making constructive comments on the manuscript.

References (192)

  • Y. Ben-Ari et al.

    Injections of kainic acid into the amygdaloid complex of the rat: an electrographic, clinical and histological study in relation to the pathology of epilepsy

    Neuroscience

    (1980)
  • Y. Ben-Ari et al.

    Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline or pentetrazole: metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy

    Neuroscience

    (1981)
  • T.L. Babb et al.

    Glutamate AMPA receptors in the fascia dentata of human and kainate rat hippocampal epilepsy

    Epilepsy Res.

    (1996)
  • M.L. Berger et al.

    Limbic seizures without brain damage after injection of low doses of kainic acid into the amygdala of freely moving rats

    Brain Res.

    (1989)
  • N. Best et al.

    Changes in parvalbumin-immunoreactive neurons in the rat hippocampus following a kainic acid lesion

    Neurosci. Lett.

    (1993)
  • E.B. Bloss et al.

    Hippocampal kainate receptors

    Vitam. Horm.

    (2010)
  • A. Bortel et al.

    Convulsive status epilepticus duration as determinant for epileptogenesis and interictal discharge generation in the rat limbic system

    Neurobiol. Dis.

    (2010)
  • M. Bortolato et al.

    Involvement of GABA in mirror focus: a case report

    Epilepsy Res.

    (2010)
  • V. Bouilleret et al.

    Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy

    Neuroscience

    (1999)
  • G. Buzsáki

    Theta oscillations in the hippocampus

    Neuron

    (2002)
  • E.A. Cavalheiro et al.

    Long-term effects of intrahippocampal kainic acid injection in rats: a method for inducing spontaneous recurrent seizures

    Electroencephalogr. Clin. Neurophysiol.

    (1982)
  • C. Cepeda et al.

    Limbic status epilepticus: behaviour and sleep alterations after intra-amygdaloid kainic acid microinjections in Papio Papio baboons

    Electroencephalogr. Clin. Neurophysiol.

    (1982)
  • E. Cherubini et al.

    Behavioral and electrographic patterns induced by systemic administration of kainic acid in developing rats

    Brain Res.

    (1983)
  • E. Cherubini et al.

    GABA: an excitatory transmitter in early postnatal life

    Trends Neurosci.

    (1991)
  • R.C. Collins et al.

    Cerebral metabolic response to systemic kainic acid: 14-C-deoxyglucose studies

    Life Sci.

    (1980)
  • S.M. Cornish et al.

    Long-term loss of paired pulse inhibition in the kainic acid-lesioned hippocampus of the rat

    Neuroscience

    (1989)
  • J.T. Coyle et al.

    Clinical, neuropathologic and pharmacologic aspects of Huntington's disease: correlates with a new animal model

    Prog. Neuropsychopharmacol.

    (1977)
  • G. Curia et al.

    The pilocarpine model of temporal lobe epilepsy

    J. Neurosci. Methods

    (2008)
  • C.J. Davenport et al.

    GABAergic neurons are spared after intrahippocampal kainate in the rat

    Epilepsy Res.

    (1990)
  • R. Dawson et al.

    Kainic acid-induced seizures in aged rats: neurochemical correlates

    Brain Res. Bull.

    (1992)
  • M. Drexel et al.

    Parvalbumin interneurons and calretinin fibers arising from the thalamic nucleus reuniens degenerate in the subiculum after kainic acid-induced seizures

    Neuroscience

    (2011)
  • M. Drexel et al.

    Sequel of spontaneous seizures after kainic acid-induced status epilepticus and associated neuropathological changes in the subiculum and entorhinal cortex

    Neuropharmacology

    (2012)
  • M. Dunleavy et al.

    Experimental neonatal status epilepticus and the development of temporal lobe epilepsy with unilateral hippocampal sclerosis

    Am. J. Pathol.

    (2010)
  • J. Engel

    Introduction to temporal lobe epilepsy

    Epilepsy Res.

    (1996)
  • J.E. Franck et al.

    Do kainate-lesioned hippocampi become epileptogenic?

    Brain Res.

    (1985)
  • E.D. French et al.

    Intrahippocampal kainic acid, seizures and local neuronal degeneration: relationships assessed in unanesthetized rats

    Neuroscience

    (1982)
  • B. Fritsch et al.

    Pathological alterations in GABAergic interneurons and reduced tonic inhibition in the basolateral amygdala during epileptogenesis

    Neuroscience

    (2009)
  • G.V. Goddard et al.

    A permanent change in brain function resulting from daily electrical stimulation

    Exp. Neurol.

    (1969)
  • K. Goffin et al.

    Cyclicity of spontaneous recurrent seizures in pilocarpine model of temporal lobe epilepsy in rat

    Exp. Neurol.

    (2007)
  • G.T. Golden et al.

    Rat strain and age differences in kainic acid induced seizures

    Epilepsy Res.

    (1995)
  • I. Gröticke et al.

    Behavioral alterations in a mouse model of temporal lobe epilepsy induced by intrahippocampal injection of kainate

    Exp. Neurol.

    (2008)
  • D. Hasegawa et al.

    Complex partial status epilepticus induced by a microinjection of kainic acid into unilateral amygdala in dogs and its brain damage

    Brain Res.

    (2002)
  • D.E. Heggli et al.

    Systemic injection of kainic acid: effect on neurotransmitter markers in piriform cortex, amygdaloid complex and hippocampus and protection by cortical lesioning and anticonvulsants

    Neuroscience

    (1982)
  • J.L. Hellier et al.

    Spontaneous motor seizures of rats with kainate-induced epilepsy: effect of time of day and activity state

    Epilepsy Res.

    (1999)
  • J.L. Hellier et al.

    Recurrent spontaneous motor seizures after repeated low-dose systemic treatment with kainate: assessment of a rat model of temporal lobe epilepsy

    Epilepsy Res.

    (1998)
  • G.L. Holmes et al.

    Effects of kainic acid on seizure susceptibility in the developing brain

    Brain Res.

    (1988)
  • M.R. Hynd et al.

    Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease

    Neurochem. Int.

    (2004)
  • S. Kar et al.

    Systemic administration of kainic acid induces selective time dependent decrease in [125I]insulin-like growth factor I, [125I]insulin-like growth factor II and [125I]insulin receptor binding sites in adult rat hippocampal formation

    Neuroscience

    (1997)
  • M. Kasugai et al.

    Differences in two mice strains on kainic acid-induced amygdalar seizures

    Biochem. Biophys. Res. Commun.

    (2007)
  • T. Araki et al.

    Characterization of neuronal death induced by focally evoked limbic seizures in the C57BL/6 mouse

    J. Neurosci. Res.

    (2002)
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