Cortical kindling induces elevated levels of AMPA and GABA receptor subunit mRNA within the amygdala/piriform region and is associated with behavioral changes in the rat Amy K. Henderson a, * , Michael A. Galic b , G. Campbell Teskey a,c a Department of Psychology, University of Calgary, Calgary, AB, Canada b Department of Neuroscience, University of Calgary, Calgary, AB, Canada c Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada article info Article history: Received 8 July 2009 Revised 14 August 2009 Accepted 15 August 2009 Available online 18 September 2009 Keywords: Seizures Kindling Epilepsy Rat Receptor Anxiety Comorbidity abstract Cortical kindling causes alterations within the motor cortex and results in long-standing motor deficits. Less attention has been directed to other regions that also participate in the epileptiform activity. We examined if cortical kindling could induce changes in excitatory and inhibitory receptor subunit mRNA in the amygdala/piriform regions and if such changes are associated with behavioral deficits. After corti- cal kindling, amygdala/piriform regions were dissected to analyze mRNA levels of NMDA, AMPA, and GABA receptor subunits using reverse transcription polymerase chain reaction, or rats were subjected to a series of behavioral tests. Kindled rats had significantly greater amounts of GluR1 and GluR2 AMPA receptor mRNA, and a1 and a2 GABA receptor subunit mRNA, compared with sham controls, which was associated with greater anxiety-like behaviors in the elevated plus maze and reduced freezing behaviors in the fear conditioning task. In summary, cortical kindling produces dynamic receptor subunit changes in regions in addition to the seizure focus. Ó 2009 Elsevier Inc. All rights reserved. 1. Introduction Kindling is a phenomenon whereby epileptiform activity per- manently increases synaptic strength within neural ensembles that are anatomically connected and electrically excitable [1–3]. The amygdala and piriform cortex appear to be critical in the gen- eration of kindling-induced seizures [1,4]. Importantly these struc- tures have dense functional interconnections with the neocortex [5,6] and consequently participate in the induction of widespread seizure-induced plasticity [1,7,8]. These changes in synaptic effi- cacy or plasticity are mediated by excitatory and inhibitory recep- tor systems distributed in the efferent and afferent connections of the structures involved. The most dominant of the transmitter systems involved are a-amino-3-hydroxy-5-methyl-4-isoxazole- propionic acid (AMPA), N-methyl-D-aspartic acid (NMDA), and c- aminobutyric acid (GABA) receptors [9–13]. Alterations in these receptors have been demonstrated in several studies using differ- ent models of seizures and epilepsy [14–18], but the directionality of the alterations appears to be dependent on the method used to induce seizures, the structure being examined, and the length of time after the seizures these receptors are being measured. The process by which the seizure focus recruits and maintains abnor- mal epileptiform activity with other brain regions over time is the topic of extensive ongoing investigation [19]. Kindling not only is a reliable model of seizures and epilepto- genesis [20], but also strongly models the pattern of abnormal interictal behaviors or behavioral comorbidities [21–23]. Interictal behavioral changes have been well modeled using the electrical kindling technique, with kindled animals showing persistently al- tered skilled motor impairment [24], anxiety-like and aggression- related behaviors [25,26], spatial memory abilities [27], as well as alterations in sex hormones and sexual function [28] depending on the kindling location and number of seizures. Typically, the extent of these interictal behavioral impairments is normally described within the context of the kindling focus [29]; however, relatively little attention has been directed to other regions in- volved in seizure spread and recruitment that may be subjected to seizure-induced modification. In this study we examined if kindling of the neocortex via the cor- pus callosum could cause epileptiform-like changes in the amygdala/ piriform region (an area of strong sensitivity to seizures) and induce molecular and behavioral alterations. This idea was derived from pre- vious studies that suggested a strong similarity between cortical (frontal) kindling- and amygdala kindling-induced seizures [30–32]. 1525-5050/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2009.08.015 * Corresponding author. Address: University of Calgary, Department of Psychol- ogy, 2500 University Drive NW, Calgary, AB, Canada T2N 1N4. E-mail address: ahender@ucalgary.ca (A.K. Henderson). Epilepsy & Behavior 16 (2009) 404–410 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh