Severity of Histopathologic Abnormalities and In Vivo Epileptogenicity in the In Utero Radiation Model of Rats Is Dose Dependent

Abstract

Summary:Purpose: Malformations of cortical development (MCDs) are a frequent cause of refractory epilepsy in humans. The in utero radiation model in rats shares many clinical and histopathologic characteristics with human MCDs. Previous studies reported the presence of clinical seizures in radiated rats, but also suggested a dose-dependent differential effect.Methods: Time-pregnant Sprague-Dawley rats were irradiated on embryonic day E17 with 100 cGy (low dose), 145 cGy (medium dose), 175 cGy (high dose), or were left untreated. Their adult litters were implanted with bifrontal epidural and hippocampal depth electrodes and underwent long-term video-EEG monitoring. After 2 weeks of monitoring, the animals were killed and their brains processed for histological studies.Results: Spikes were most frequently found in the rats that were subjected to low-and medium-dose radiation at E17 and were less frequently seen in the animals that were subjected to high-dose radiation. No interictal spikes were found in any of the control animals. Seizures were recorded in three of five animals of the medium-dose group. Histological studies showed a dosedependent decrease in cortical thickness as well as an increase of cortical and hippocampal disorganization.Conclusions: In vivo epileptogenicity in radiated animals was present only in mild or moderate MCD. No in vivo epileptogenicity was seen in severe radiation-induced MCD. Key Words: Cortical dysplasia-In utero irradiationElectroencephalography-Dose dependent.Malformations of cortical development (MCDs) in the context of refractory epilepsy were described for the first time >30 years ago (1). With the improvement in imaging techniques, it has become evident that the various types of MCDs account for a large number of patients with refractory focal epilepsy (2-4). Surgery in patients with MCDs has a less favorable outcome than does surgery in patients with hippocampal sclerosis (5,6).Comparatively, little is known about the mechanisms leading to epileptogenicity in MCDs. Several animal models of MCDs have been established, such as the focal freeze lesion model (7,8), the in utero alkylating model (9), and the in utero irradiation model (10). All models share important histopathologic and in vitro electrophysiological characteristics of human focal MCDs (11,12). Spontaneous epileptic seizures have been reported in some genetic models of MCDs [e.g., the p35 knockout mouse (13) and the telencephalic internal structural heterotopia (TISH) rat (14)]. Among the injury-inducing models, sysAccepted January 25, 2004. Address correspondence and reprint requests to Dr. I.M. Najm at Section of Epilepsy, 9500 Euclid Avenue, S51, Cleveland, OH 44195, U.S.A. E-mail: najmi@ccf.org tematic long-term EEG monitoring has been performed only in the in utero irradiation model (15). We previously demonstrated that four of the seven rats exposed to 145 cGy in utero, but none of the control rats, exhibited spontaneous seizures. In addition, all radiated rats, but none of the normal controls, had frequen...

LIS1 Deficiency Promotes Dysfunctional Synaptic Integration of Granule Cells Generated in the Developing and Adult Dentate Gyrus

“…The convergence of these features in a mouse model could have significant consequences for circuit information processing and/or contribute to the generation of pathological network excitability associated with type I lissencephaly. A number of genetically based animal models of MCD have been developed, and most show robust hyperexcitability and/or spontaneous seizures (Wenzel et al, 2001;Kellinghaus et al 2004;Patel et al, 2004;Kwon et al, 2006;Harrington et al, 2007;Patrylo and Willingham, 2007;Nosten-Bertrand et al, 2008;Greenwood et al, 2009;Kerjan et al, 2009). When synaptic mechanisms have been investigated, these studies have typically reported postsynaptic alterations in glutamatergic excitatory Auerbach et al, 2011;Bateup et al, 2011;Luikart et al, 2011) or GABAergic inhibitory currents (Trotter et al, 2006;Ackman et al, 2009).…”

Dysfunction of Synaptic Inhibition in Epilepsy Associated with Focal Cortical Dysplasia

“…Furthermore, this decreased inhibition, even in the absence of additional defects, could be sufficient for the generation of seizures, because even small reductions in GABA-mediated function were shown to induce abnormal electrical discharge (Powell et al, 2003;Cobos et al, 2005). Interestingly, a reduction in IPSC frequency was reported in a rodent model of cortical dysplasia (caused by prenatal irradiation) featuring hyperexcitability and rare spontaneous seizures (Zhu and Roper, 2000;Chen and Roper, 2003;Kellinghaus et al, 2004). In both human tissue and experimental models, this reduced IPSC frequency could result from a decreased release of GABA at presynaptic terminals or simply from an impairment of GABAergic terminals and/or cells within the FCD.…”

Basic mechanisms of MCD in animal models

“…Therefore, in utero irradiation is an injury-based model of diffuse cortical malfomation similar to type I FCD, according to the Palmini classification system (Palmini et al , 2004). Spontaneous seizures have been previously described in these animals (Kellinghaus et al , 2004). …”