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Open Access Research article

Disruption of the NF-κB/IκBα Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons

David J Shim123, Li Yang1, J Graham Reed5, Jeffrey L Noebels245, Paul J Chiao6 and Hui Zheng124*

Author Affiliations

1 Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA

2 Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA

3 Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA

4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA

5 Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA

6 Department of Surgical Oncology-Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA

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Molecular Neurodegeneration 2011, 6:42  doi:10.1186/1750-1326-6-42

Published: 10 June 2011

Abstract

Background

Though originally discovered in the immune system as an important mediator of inflammation, NF-κB has recently been shown to play key roles in the central nervous system, such as synaptogenesis, synaptic plasticity, and cognition. NF-κB activity is normally tightly regulated by its primary inhibitor, IκBα, through a unique autoinhibitory loop. In this study, we tested the hypothesis that the IκBα autoinhibitory loop ensures optimal levels of NF-κB activity to promote proper brain development and function. To do so, we utilized knock-in mice which possess mutations in the IκBα promoter to disrupt the autoinhibitory loop (IκBαM/M KI mice).

Results

Here, we show that these mutations delay IκBα resynthesis and enhance NF-κB activation in neurons following acute activating stimuli. This leads to improved cognitive ability on tests of hippocampal-dependent learning and memory but no change in hippocampal synaptic plasticity. Instead, hippocampal neurons from IκBαM/M KI mice form more excitatory and less inhibitory synapses in dissociated cultures and are hyperexcitable. This leads to increased burst firing of action potentials and the development of abnormal hypersynchronous discharges in vivo.

Conclusions

These results demonstrate that the IκBα autoinhibitory loop is critical for titrating appropriate levels of endogenous NF-κB activity to maintain proper neuronal function.