期刊
JOURNAL OF NEUROSCIENCE
卷 27, 期 11, 页码 2999-3009出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4913-06.2007
关键词
STEP; ERK/MAPK; cell death; apoptosis; hippocampus; seizure; somatostatin
资金
- NIMH NIH HHS [R01 MH062335, MH52711, MH62335, R01 MH052711, R01 MH052711-13, K02 MH001527-08, K02 MH001527, MH01527] Funding Source: Medline
- NINDS NIH HHS [5P30NS045758, NS47176, R01 NS042826-05, P30 NS045758, NS42826, R01 NS042826, R01 NS047176] Funding Source: Medline
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 somatostat-inergic hilar interneurons vulnerable to SE-induced cell death.
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