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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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

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Figure 6

NFI-A–deficient neurons are sensitive to NMDA receptor activation.

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NFI-A–deficient neurons are sensitive to NMDA receptor activation. (A) G...
(A) Genotyping of embryos whose brains were used for cortical cultures. (B) NFI-A expression in day 10 in vitro neuronal cultures with different genotypes. (C) Cortical cultures dissociated from Nfia+/+, Nfia+/–, and Nfia–/– embryos were treated with either CSS or 50 μM NMDA. Experiments were replicated at least 3 times. *P < 0.01, 1-way ANOVA followed by Tukey-Kramer post-hoc test. (D) Nfia–/– neurons were treated with CSS with or without MK801 (10 μM), APV (250 μM), 6-cyano-7-nitroquinoxaline-2,3,-dione (CNQX) (400 μM), TTX (2 μM), or CSS with calcium replaced by cobalt (–Ca2+). *P < 0.01 compared with CSS mock treatment, 1-way ANOVA followed by Tukey-Kramer post-hoc test. Experiments were replicated 3 times. (E) The increased sensitivity of Nfia–/– neurons is rescued by Ad.HA-NFI-A1.1–mediated NFI-A overexpression in primary cortical cultures. Experiments were replicated 3 times. *P < 0.01, Student’s t test, compared with Nfia–/– neurons transduced with GFP adenovirus.