NMDA-induced neuronal survival is mediated through nuclear factor I-A in mice
Sika Zheng, … , Ted M. Dawson, Valina L. Dawson
Sika Zheng, … , Ted M. Dawson, Valina L. Dawson
Published June 1, 2010
Citation Information: J Clin Invest. 2010;120(7):2446-2456. https://doi.org/10.1172/JCI33144.
View: Text | PDF
Research Article Neuroscience Article has an altmetric score of 3

NMDA-induced neuronal survival is mediated through nuclear factor I-A in mice

Abstract

Identification of the signaling pathways that mediate neuronal survival signaling could lead to new therapeutic targets for neurologic disorders and stroke. Sublethal doses of NMDA can induce robust endogenous protective mechanisms in neurons. Through differential analysis of primary library expression and microarray analyses, here we have shown that nuclear factor I, subtype A (NFI-A), a member of the NFI/CAAT-box transcription factor family, is induced in mouse neurons by NMDA receptor activation in a NOS- and ERK-dependent manner. Knockdown of NFI-A induction using siRNA substantially reduced the neuroprotective effects of sublethal doses of NMDA. Further analysis indicated that NFI-A transcriptional activity was required for the neuroprotective effects of NMDA receptor activation. Additional evidence of the neuroprotective effects of NFI-A was provided by the observations that Nfia–/– neurons were highly sensitive to NMDA-induced excitotoxicity and were more susceptible to developmental cell death than wild-type neurons and that Nfia+/– mice were more sensitive to NMDA-induced intrastriatal lesions than were wild-type animals. These results identify NFI-A as what we believe to be a novel neuroprotective transcription factor with implications in neuroprotection and neuronal plasticity following NMDA receptor activation.

Authors

Sika Zheng, Stephen M. Eacker, Suk Jin Hong, Richard M. Gronostajski, Ted M. Dawson, Valina L. Dawson

×

Figure 1

NFI-A is induced by neuroprotective models in vitro.

Options: View larger image (or click on image) Download as PowerPoint
NFI-A is induced by neuroprotective models in vitro. (A) Induction of Nf...
(A) Induction of Nfia mRNA splice variants (left) and total Nfia mRNA (right) upon 50 μM NMDA (5 minutes) treatment in primary cortical cultures. Message levels were measured by quantitative real-time PCR using isoform-specific primer sets. Total Nfia mRNA was measured in at least 3 independent experiments, with mRNA levels normalized relative to Gapdh internal control. (B) Immunoblot analysis of the induction of NFI-A following a 5-minute 50 μM NMDA treatment of primary cortical cultures with or without the MEK inhibitor U0126 (50 μM), the NOS inhibitor nitro-l-arginine (L-NNA, 100 μM), or the NMDA receptor antagonist APV (250 μM) applied 30 minutes before 50 μM NMDA treatment. (C) Quantification of NFI-A levels was normalized to β-tubulin expression. Experiments were replicated at least 3 times; *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA followed by Tukey-Kramer post-hoc test. (D) Immunocytochemical staining of cortical cultures at 0, 3, and 24 hours after 5-minute 50 μM NMDA treatment shows induction of NFI-A only in neurons (MAP2+), which is blocked by APV (250 μM). Note that the increased intensity of NFI-A staining in MAP2+ cells and staining in non-neuronal cells (arrows) does not change following NMDA treatment. These data are representative of 3 separate experiments. Scale bar: 50 μm.