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.
Autophagy Hippocampus Brain Neurodegeneration Mouse Status epilepticus Kainic acid Kainate
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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.
DeLorenzo RJ, Pellock JM, Towne AR, Boggs JG (1995) Epidemiology of status epilepticus. J Clin Neurophysiol 12:316–325CrossRefPubMedGoogle Scholar
Smith BN, Dudek FE (2001) Short- and long-term changes in CA1 network excitability after kainate treatment in rats. J Neurophysiol 85:1–9CrossRefPubMedGoogle Scholar
Schauwecker PE (2002) Complications associated with genetic background effects in models of experimental epilepsy. Prog Brain Res 135:139–148CrossRefPubMedGoogle Scholar
Schauwecker PE, Steward O (1997) Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc Natl Acad Sci U S A 94:4103–4410CrossRefPubMedPubMedCentralGoogle Scholar
Kurschner VC, Petruzzi RL, Golden GT, Berrettini WH, Ferraro TN (1998) Kainate and AMPA receptor binding in seizure-prone and seizure-resistant inbred mouse strains. Brain Res 780:1–8CrossRefPubMedGoogle Scholar
Steward O, Schauwecker PE, Guth L, Zhang Z, Fujiki M, Inman D et al (1999) Genetic approaches to neurotrauma research: opportunities and potential pitfalls of murine models. Exp Neurol 157:19–42CrossRefPubMedGoogle Scholar
Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477CrossRefPubMedGoogle Scholar
Liu L, Hamre KM, Goldowitz D (2012) Kainic acid-induced neuronal degeneration in hippocampal pyramidal neurons is driven by both intrinsic and extrinsic factors: analysis of FVB/N↔C57BL/6 chimeras. J Neurosci 32:12093–12101CrossRefPubMedGoogle Scholar
Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036CrossRefPubMedGoogle Scholar
Rami A, Kögel D (2008) Apoptosis meets autophagy-like cell death in the ischemic penumbra: two sides of the same coin? Autophagy 4:422–426CrossRefPubMedGoogle Scholar
Nikoletopoulou V, Markaki M, Palikaras K, Tavernarakis N (2013) Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta 1833:3448–3459CrossRefPubMedGoogle Scholar
Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889CrossRefPubMedGoogle Scholar
Steiger-Barraissoul S, Rami A (2009) Serum deprivation induced autophagy and predominantly an AIF-dependent apoptosis in hippocampal HT22 neurons. Apoptosis 14:1274–1288CrossRefPubMedGoogle Scholar
Rami A (2009) Review: autophagy in neurodegeneration: firefighter and/or incendiarist? Neuropathol Appl Neurobiol 35:449–461CrossRefPubMedGoogle Scholar
Fekadu J, Rami A (2016) Beclin-1 deficiency alters autophagosome formation, lysosome biogenesis and enhances neuronal vulnerability of HT22 hippocampal cells. Mol Neurobiol 53:5500–5509CrossRefPubMedGoogle Scholar
Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884CrossRefPubMedGoogle Scholar
Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B et al (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 118:2190–2199PubMedPubMedCentralGoogle Scholar
D'Amelio M, Sheng M, Cecconi F (2012) Caspase-3 in the central nervous system: beyond apoptosis. Trends Neurosci 35:700–709CrossRefPubMedGoogle Scholar