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The Journal of Neuroscience, October 15, 2003, 23(28):9403-9408
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BRIEF COMMUNICATION
Forebrain-Specific Neuronal Inhibition of Nuclear Factor- B Activity Leads to Loss of Neuroprotection
Valérie Fridmacher,1 *
Barbara Kaltschmidt,3 *
Bertrand Goudeau,1
Delphine Ndiaye,1
Francesco Mattia Rossi,2
Julia Pfeiffer,3
Christian Kaltschmidt,3
Alain Israël,1 and
Sylvie Mémet1
1Unité de Biologie Moléculaire de l'Expression Génique, Unité de Recherche Associée Centre National de la Recherche Scientifique 2582, 2Unité Récepteurs et Cognition, Centre National de la Recherche Scientifique Unité de Recherche Associée 2182, Institut Pasteur, 75724 Paris Cedex 15, France, and 3University of Witten/Herdecke Institut für Neurobiochemie, 58448 Witten, Germany
The transcription factor Rel/nuclear factor (NF)- B is known for its fundamental role in regulating immune and inflammatory responses. In the brain, constitutive NF-B activity has been detected exclusively in neurons, and a large diversity of stimuli have been reported to induce NF-B activity. Yet the function of this transcription factor in the nervous system remains unclear, and its role in neuroprotection or neurodegeneration is open to debate. Recently it was suggested that B-driven gene expression in neurons is controlled by Sp1-like factors. To clarify such controversy, we have characterized here a novel mouse model in which the entire NF-B-dependent transcriptional response is abolished in the forebrain. Calcium-calmodulin-dependent kinase II  promoter-driven tetracycline transactivator was used for regulated expression of a transdominant negative mutant of inhibitor B (super-repressor) together with a green fluorescent protein tracer. Inhibition of expression of a B-dependent lacZ transgene was shown in triple transgenic mice, which correlated with the loss of B-specific DNA binding. In transgenic organotypic hippocampal slice cultures, expression of the super-repressor led to strong cell death after neurotoxic insults. These data demonstrate for the first time that neuron-restricted ablation of NF-B-driven gene expression increases neurodegeneration. This might lead to the path for new treatments of neurodegenerative diseases.
Key words: transcription factor NF-B; brain; tetracycline; neuroprotection; organotypic hippocampal slice cultures; kainate; ferrous sulfate; transgenic mice
Received Feb 6, 2003;
revised August 20, 2003;
accepted August 28, 2003.
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