Systemic Injection of Kainic Acid Differently Affects LTP Magnitude Depending on its Epileptogenic Efficiency

Luz M Suárez,Daniel Gómez-Domínguez,Marion Inostroza,Elena Cid,Liset Menéndez De La Prida,Jorge R Brotons-Mas,Beatriz Gal,José M Solís,Anthony E Kline

doi:10.1371/journal.pone.0048128

Abstract

Seizures have profound impact on synaptic function and plasticity. While kainic acid is a popular method to induce seizures and to potentially affect synaptic plasticity, it can also produce physiological-like oscillations and trigger some forms of long-term potentiation (LTP). Here, we examine whether induction of LTP is altered in hippocampal slices prepared from rats with different sensitivity to develop status epilepticus (SE) by systemic injection of kainic acid. Rats were treated with multiple low doses of kainic acid (5 mg/kg; i.p.) to develop SE in a majority of animals (72–85% rats). A group of rats were resistant to develop SE (15–28%) after several accumulated doses. Animals were subsequently tested using chronic recordings and object recognition tasks before brain slices were prepared for histological studies and to examine basic features of hippocampal synaptic function and plasticity, including input/output curves, paired-pulse facilitation and theta-burst induced LTP. Consistent with previous reports in kindling and pilocapine models, LTP was reduced in rats that developed SE after kainic acid injection. These animals exhibited signs of hippocampal sclerosis and developed spontaneous seizures. In contrast, resistant rats did not become epileptic and had no signs of cell loss and mossy fiber sprouting. In slices from resistant rats, theta-burst stimulation induced LTP of higher magnitude when compared with control and epileptic rats. Variations on LTP magnitude correlate with animals’ performance in a hippocampal-dependent spatial memory task. Our results suggest dissociable long-term effects of treatment with kainic acid on synaptic function and plasticity depending on its epileptogenic efficiency.

Highlights

Seizures have profound physiological and neurological sequelae
We found a group of rats resistant to develop status even after several accumulated doses of kainate
Using multiple low doses (5 mg/kg) of kainic acid resulted in the development of status epilepticus in a majority of both Wistar (n = 82 out of 96, 85%) and Sprague-Dawley rats (n = 41 out of 57, 72%)

Summary

Introduction

Seizures have profound physiological and neurological sequelae. Recurrent seizures and status epilepticus presumably trigger an initial cascade of events including kinase activation, oxidative stress, neuronal damage and glial activation that change cellular and synaptic function [1]. In the particular case of synaptic function, seizures affect cellular processes accompanying a form of plasticity, namely long-term potentiation (LTP). Electrophysiological studies in animal models of epilepsy show that repeated seizures have deleterious consequences on LTP [3,4]. Such effects have been proposed to be linked to the saturation of synaptic responses or due to impairment of LTP-associated molecular mechanisms caused by epileptiform bursts of activity [5,6,7,8]. Seizure-induced saturation of cellular resources available for plasticity would in turn potentially affect memory function [9,10,11]

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Conclusion