Elsevier

Neuroscience

Volume 156, Issue 1, 22 September 2008, Pages 222-237
Neuroscience

Systems neuroscience
Dynamic seizure-related changes in extracellular signal-regulated kinase activation in a mouse model of temporal lobe epilepsy

https://doi.org/10.1016/j.neuroscience.2008.07.010Get rights and content

Abstract

Extracellular signal-regulated kinase (ERK) is highly sensitive to regulation by neuronal activity and is critically involved in several forms of synaptic plasticity. These features suggested that alterations in ERK signaling might occur in epilepsy. Previous studies have described increased ERK phosphorylation immediately after the induction of severe seizures, but patterns of ERK activation in epileptic animals during the chronic period have not been determined. Thus, the localization and abundance of phosphorylated extracellular signal-regulated kinase (pERK) were examined in a pilocarpine model of recurrent seizures in C57BL/6 mice during the seizure-free period and at short intervals after spontaneous seizures. Immunolabeling of pERK in control animals revealed an abundance of distinctly-labeled neurons within the hippocampal formation. However, in pilocarpine-treated mice during the seizure-free period, the numbers of pERK-labeled neurons were substantially decreased throughout much of the hippocampal formation. Double labeling with a general neuronal marker suggested that the decrease in pERK-labeled neurons was not due primarily to cell loss. The decreased ERK phosphorylation in seizure-prone animals was interpreted as a compensatory response to increased neuronal excitability within the network. Nevertheless, striking increases in pERK labeling occurred at the time of spontaneous seizures and were evident in large populations of neurons at very short intervals (as early as 2 min) after detection of a behavioral seizure. These findings suggest that increased pERK labeling could be one of the earliest immunohistochemical indicators of neurons that are activated at the time of a spontaneous seizure.

Section snippets

Animals and pilocarpine treatment

The pilocarpine mouse model of recurrent seizures has been described in detail in previous studies (Peng et al 2004, Peng and Houser 2005). Briefly, young adult (6–8 weeks of age) C57BL/6 male mice (20–27 g; Harlan, Indianapolis, IN, USA) were used, and sustained seizures were induced in experimental animals by the administration of pilocarpine, a muscarinic cholinergic agonist. Animals were divided randomly into experimental and control groups, and all were injected with scopolamine methyl

Patterns of pERK labeling in control mice

Previous studies have described the distribution and abundance of ERK1/2 proteins and their mRNAs in the hippocampal formation (Fiore et al 1993, Thomas and Hunt 1993, Flood et al 1998). However, descriptions of the basal patterns of activated (phosphorylated) ERK are limited and have emerged primarily from descriptions of control tissue in studies of ERK activation following experimental manipulations. More detailed descriptions of the normal patterns of pERK labeling were needed in rostral

Discussion

This study demonstrated several unique features of pERK labeling in control and epileptic animals. First, in contrast to expected low levels of activated ERK in control mice, distinct pERK labeling was present in a sizeable subset of neurons throughout the hippocampal formation. Second, neuronal pERK labeling was strikingly decreased in pilocarpine-treated animals compared with controls during the periods between spontaneous seizures. Interestingly, this decrease in pERK labeling extended

Acknowledgments

This work was supported by Veterans Affairs Medical Research Funds (C.R.H.) and National Institutes of Health grant NS046524 (C.R.H.). We thank Christine Farrar for conducting the Western blot analyses, Yliana Cetina for expert assistance with the seizure monitoring, and Drs. Tom O'Dell and Istvan Mody for helpful discussions.

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