ReviewThe kainic acid model of temporal lobe epilepsy
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.
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