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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.
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Research Article Neuroscience Article has an altmetric score of 3

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

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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

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Figure 2

Blocking NFI-A induction by 50 μM NMDA neuroprotective treatment significantly inhibits its protective effects.

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Blocking NFI-A induction by 50 μM NMDA neuroprotective treatment signifi...
(A) Knockdown of ectopic NFI-A expression by NFI-A siRNAs (1, 2, and 3) in HeLa cells. SCR, scrambled control siRNA. siRNA and NFI-A expression plasmid were cotransfected into HeLa cells. Twenty-four hours after transfection, NFI-A expression levels were examined from total cell lysates. These experiments were replicated 3 times. (B) Immunoblot analysis of blockade of NFI-A induction by 50 μM NMDA treatment using NFI-A siRNA 3, but not by SCR siRNA or DsRed siRNA molecules. Cortical cultures were transfected with siRNA 1 day and 3 days prior to 50 μM NMDA treatment and were harvested 24 hours after NMDA treatment. Experiments were replicated 3 times. (C) Quantification of NFI-A levels. *P < 0.01, 1-way ANOVA followed by Tukey-Kramer post-hoc test. (D) Neuronal viability after 500 μM NMDA excitotoxicity in cortical cultures. siRNAs were transfected twice at 3 days and 1 day prior to 50 μM NMDA treatment. The cultures were challenged with 500 μM NMDA toxicity for 5 minutes at 24 hours after the 5-minute 50 μM NMDA treatment. Experiments were replicated at least 3 times, with at least 6,000 neurons counted per experiment. NFI-A siRNA treatment (right gray bar) significantly blocks the protective effects of 50 μM NMDA against 500 μM NMDA treatment. *P < 0.01, 1-way ANOVA followed by Tukey-Kramer post-hoc test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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