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The Journal of Neuroscience, August 9, 2006, 26(32):8295-8304; doi:10.1523/JNEUROSCI.1986-05.2006
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Neurobiology of Disease
c-Jun N-Terminal Kinase Activation Responses Induced by Hippocampal Kindling Are Mediated by Reactive Astrocytes
Kasie K. Cole-Edwards, Alberto E. Musto, andNicolas G. Bazan Louisiana State University Neuroscience Center of Excellence, Louisiana State University Health Sciences Center School of Medicine, New Orleans, Louisiana 70112
Correspondence should be addressed to Nicolas G. Bazan, Louisiana State University Neuroscience Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112. Email: nbazan{at}lsuhsc.edu
Hippocampal kindling, a model of mesial temporal lobe epilepsy, is developed through repetitive stimulation of the hippocampus and leads to increased after-discharges as measured by EEG and an enduring seizure-prone state. Synthesis of new proteins is thought to form the basis for sustained seizure-induced physiological and/or pathological changes in synaptic reorganization and apoptotic/necrotic neuronal death. Here we examined the effect of kindling on stimulus-induced c-Jun N-terminal kinase (JNK) and p38 phosphorylation, events postulated to lie upstream of seizure-induced changes in gene transcription. We found that stimulus-induced phosphorylation of JNK, but not of p38, is significantly enhanced in kindled animals compared with their naive counterparts in the CA1 subregion of the hippocampus. Immunofluorescent staining confirmed this region-specific pattern of JNK activation and revealed that reactive astrocytes mediate this effect. Astrocyte proliferation and hypertrophy, as well as upregulation of vimentin protein levels, common markers of astrogliosis, were present after 4 d of kindling. Moreover, this reactive astrogliosis was associated with neuronal death as visualized with Fluoro-jade B and anti-active caspase-3 staining. Stimulus-induced phosphorylation of the JNK substrate paxillin was enhanced in kindled animals, but not that of c-Jun. Moreover, a pan-antibody against MAPK/CDK (mitogen-activated protein kinases/cyclin-dependent kinase) substrates indicated the presence of phosphorylated proteins in cytosolic, membrane, and nuclear fractions. The consequence of these phosphorylation events is not completely understood, but these findings suggest a selective astrocytic signaling response to aberrant synaptic activity, signaling that may modulate kindling progression and/or neuronal death.
Key words: epileptogenesis; kindling; hippocampus; c-Jun N-terminal kinase; JNK; p38; reactive astrogliosis
Received March 14, 2005; revised July 7, 2006; accepted July 7, 2006.
Correspondence should be addressed to Nicolas G. Bazan, Louisiana State University Neuroscience Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112. Email: nbazan{at}lsuhsc.edu
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