Abstract
BackgroundIn epilepsy, seizures are generated by abnormal synchronous activity in neurons. In the rat hippocampus (HIP), epileptiform activity has been found to be associated with gap junctions (GJs). GJs are formed by the combination of two hemichannels, each composed of six connexins. At low doses, the convulsive drug 4-aminopyridine (4-AP) produces epileptiform activity without affecting glutamate levels; therefore, GJs could participate in its effect. Based on this argument, in this study, the expression of Cx 32, Cx 36 and Cx 43 protein and mRNA in the HIP of rats treated with 4-AP was evaluated. The evaluation of connexins was carried out by chemifluorescent immunoassay, semiquantitative RT-PCR and immunofluorescence to detect the amount and distribution of connexins and of cellular markers in the HIP and dentate gyrus (DG) of animals treated with NaCl and 4-AP in the right entorhinal cortex. In these animals, convulsive behavior and EEG signals were analyzed.ResultsThe animals treated with 4-AP showed convulsive behavior and epileptiform activity 60 min after the administration. A significant increase in the protein expression of Cx 32, Cx 36 and Cx 43 was found in the HIP contralateral and ipsilateral to the site of 4-AP administration. A trend toward an increase in the mRNA of Cx 32 and Cx 43 was also found. An increase in the cellular density of Cx 32 and Cx 43 was found in the right HIP and DG, and an increase in the cellular density of oligodendrocytes in the DG and a decrease in the number of cells marked with NeuN were observed in the left HIP.ConclusionsCx 32 and Cx 43 associated with oligodendrocytes and astrocytes had an important role in the first stages of seizures induced by 4-AP, whereas Cx36 localized to neurons could be associated with later stages. Additionally, these results contribute to our understanding of the role of connexins in acute seizures and allow us to direct our efforts to other new anticonvulsant strategies for seizure treatment.
Highlights
In epilepsy, seizures are generated by abnormal synchronous activity in neurons
Low doses of 4-AP have been observed to produce epileptiform activity without affecting glutamate levels [43, 44], suggesting that other mechanisms could be involved in seizure generation in this model, such as gap junctions (GJs). For this reason and because there have not been any studies that have addressed these issues, in the present study we evaluated protein and mRNA expression of Cxs 32, 36 and 43 in the hippocampus and dentate gyrus (DG) of freely moving rats treated with 4-AP in the right entorhinal cortex
The group of rats that received an injection of 4-AP into the right entorhinal cortex (rEC) developed epileptiform activity that was initially characterized by hypersynchronous activity, followed by trains of poly-spikes that increased in amplitude and frequency during the experiment
Summary
Seizures are generated by abnormal synchronous activity in neurons. In the rat hippocampus (HIP), epileptiform activity has been found to be associated with gap junctions (GJs). The convulsive drug 4-aminopyridine (4-AP) produces epileptiform activity without affecting glutamate levels; GJs could participate in its effect. Based on this argument, in this study, the expression of Cx 32, Cx 36 and Cx 43 protein and mRNA in the HIP of rats treated with 4-AP was evaluated. There is electrical coupling between hippocampal cells and in the entorhinal cortex [37,38,39] These limbic structures have a role in the hypersynchronization that underlies epileptiform activity, and these brain regions are important sites for seizure generation [12, 20, 40]
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