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Exclusive Activation of Caspase-3 in Mossy Fibers and Altered Dynamics of Autophagy Markers in the Mice Hippocampus upon Status Epilepticus Induced by Kainic Acid

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Abstract

Epileptic seizures are generally associated with pathological changes in the hippocampus such as astrogliosis, mossy fiber sprouting, and neuronal damage. However, more than 30% of temporal lobe epilepsy in humans shows neither neuronal damage nor mossy fiber sprouting despite chronic epileptic seizures. A similar situation exists in certain commonly used strains of mice, specifically C57BL/6 and BALB/c, which exhibit epileptic seizures, but no neuronal damage upon kainic acid administration. This suggests that intrinsic factors may influence the pathological manifestations of epilepsy. Mechanisms which are behind the resistance of hippocampal cells to KA-induced neuronal death are unknown. Autophagy seems to be involved in the pathogenesis of many brain insults and to have a dual nature in neuroprotection and cell death. This study addresses the role of autophagy upon status epilepticus (SE) that has been induced by kainic acid (KA) in the C57BL/6 strain which is classified as seizure resistant. We analyzed the dynamics in the expression of autophagic and cell death markers in the hippocampus upon SE. Immunofluorescence data show that KA did not induce neuronal death in the hippocampal CA1–CA3 subfields; however, it leads to an exclusive activation of caspase-3 in the mossy fibers. We also found alterations in the expression of core proteins of the autophagic machinery. Levels of MAP1LC3, phospho-mTOR/mTOR, and Beclin 1 were significantly increased after induction of seizures. However, levels of Atg3, Atg14, Atg5-Atg12, Atg7, BAG3, Hsp70, and LAMP1 showed no significant alterations compared to controls. Although KA did not induce neuronal death, this study provides morphological and biochemical evidence that status epilepticus induced by KA activates caspase-3 in mossy fibers and induces autophagy in the C57BL/6 hippocampus. These data indicate that autophagic factors may modulate the sensitivity of pyramidal cells to KA and that autophagy may constitute a part of an endogenous neuroprotective arsenal which might be behind the resistance of C57BL/6-hippocampal cells to KA-induced neuronal death.

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Acknowledgements

This work was supported by the Adolf-Messer-Stiftung (grant to A. Rami—“Molecular mechanisms of autophagy”). We thank Alena Konoplew for the technical assistance. A.P. Benz was supported partly by the AMS and the FPF (Frankfurter Promotionsförderung). We thank Professor J. Stehle for support of our work.

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  1. Institut für Zelluläre und Molekulare Anatomie (Anatomie III), Universitätsklinikum, Theodor-Stern-Kai 7, 60590, Frankfurt/Main, Germany

    A. Rami & A. Benz

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  1. A. Rami
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  2. A. Benz
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Correspondence to A. Rami.

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Rami, A., Benz, A. Exclusive Activation of Caspase-3 in Mossy Fibers and Altered Dynamics of Autophagy Markers in the Mice Hippocampus upon Status Epilepticus Induced by Kainic Acid. Mol Neurobiol 55, 4492–4503 (2018). https://doi.org/10.1007/s12035-017-0665-5

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  • DOI: https://doi.org/10.1007/s12035-017-0665-5

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