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The Journal of Neuroscience, March 14, 2007, 27(11):2999-3009; doi:10.1523/JNEUROSCI.4913-06.2007

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Cellular/Molecular
Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase

Yun-Sik Choi,¹ Stanley L. Lin,² Boyoung Lee,¹ Pradeep Kurup,³ Hee-Yeon Cho,¹ Janice R. Naegele,² Paul J. Lombroso,³ and Karl Obrietan¹

¹Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, ²Department of Biology, Wesleyan University, Middletown, Connecticut 06459, and ³Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520

Correspondence should be addressed to Karl Obrietan, Department of Neuroscience, Ohio State University, Graves Hall, Room 4118, 333 West 10th Avenue, Columbus, OH 43210. Email: obrietan.1{at}osu.edu

Excitotoxic cell death is one of the precipitating events in the development of temporal lobe epilepsy. Of particular prominence is the loss of GABAergic hilar neurons. Although the molecular mechanisms responsible for the selective vulnerability of these cells are not well understood, activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway has been implicated in neuroprotective responses to excitotoxicity in other neuronal populations. Here, we report that high levels of the striatal-enriched protein tyrosine phosphatase (STEP), a key regulator of ERK/MAPK signaling, are found in vulnerable somatostatin-immunoreactive hilar interneurons. Under both control conditions and after pilocarpine-induced status epilepticus (SE), ERK/MAPK activation was repressed in STEP-immunoreactive hilar neurons. This contrasts with robust SE-induced ERK/MAPK activation in the granule cell layer of the dentate gyrus, a cell region that does not express STEP. During pilocarpine-induced SE, in vivo disruption of STEP activity allowed activation of the MAPK pathway, leading to immediate-early gene expression and significant rescue from cell death. Thus, STEP increases the sensitivity of neurons to SE-induced excitotoxicity by specifically blocking a latent neuroprotective response initiated by the MAPK pathway. These findings identify a key set of signaling events that render somatostatinergic hilar interneurons vulnerable to SE-induced cell death.

Key words: STEP; ERK/MAPK; cell death; apoptosis; hippocampus; seizure; somatostatin

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Received Nov. 12, 2006; revised Feb. 1, 2007; accepted Feb. 2, 2007.

Correspondence should be addressed to Karl Obrietan, Department of Neuroscience, Ohio State University, Graves Hall, Room 4118, 333 West 10th Avenue, Columbus, OH 43210. Email: obrietan.1{at}osu.edu

This article has been cited by other articles:

				J. Xu, P. Kurup, Y. Zhang, S. M. Goebel-Goody, P. H. Wu, A. H. Hawasli, M. L. Baum, J. A. Bibb, and P. J. Lombroso Extrasynaptic NMDA Receptors Couple Preferentially to Excitotoxicity via Calpain-Mediated Cleavage of STEP J. Neurosci., July 22, 2009; 29(29): 9330 - 9343. [Abstract] [Full Text] [PDF]

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