Disruption of the NF-κB/IκBα Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons
<p>Abstract</p> <p>Background</p> <p>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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2011-06-01
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| Series: | Molecular Neurodegeneration |
| Online Access: | http://www.molecularneurodegeneration.com/content/6/1/42 |
| _version_ | 1818257728598966272 |
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| author | Noebels Jeffrey L Reed J Yang Li Shim David J Chiao Paul J Zheng Hui |
| author_facet | Noebels Jeffrey L Reed J Yang Li Shim David J Chiao Paul J Zheng Hui |
| author_sort | Noebels Jeffrey L |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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 (IκBα<sup>M/M </sup>KI mice).</p> <p>Results</p> <p>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 IκBα<sup>M/M </sup>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 <it>in vivo</it>.</p> <p>Conclusions</p> <p>These results demonstrate that the IκBα autoinhibitory loop is critical for titrating appropriate levels of endogenous NF-κB activity to maintain proper neuronal function.</p> |
| first_indexed | 2024-12-12T17:48:16Z |
| format | Article |
| id | doaj.art-5850dc3d9f6e459c8c0cd18133578afc |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-12T17:48:16Z |
| publishDate | 2011-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-5850dc3d9f6e459c8c0cd18133578afc2022-12-22T00:16:53ZengBMCMolecular Neurodegeneration1750-13262011-06-01614210.1186/1750-1326-6-42Disruption of the NF-κB/IκBα Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal NeuronsNoebels Jeffrey LReed JYang LiShim David JChiao Paul JZheng Hui<p>Abstract</p> <p>Background</p> <p>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 (IκBα<sup>M/M </sup>KI mice).</p> <p>Results</p> <p>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 IκBα<sup>M/M </sup>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 <it>in vivo</it>.</p> <p>Conclusions</p> <p>These results demonstrate that the IκBα autoinhibitory loop is critical for titrating appropriate levels of endogenous NF-κB activity to maintain proper neuronal function.</p>http://www.molecularneurodegeneration.com/content/6/1/42 |
| spellingShingle | Noebels Jeffrey L Reed J Yang Li Shim David J Chiao Paul J Zheng Hui Disruption of the NF-κB/IκBα Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons Molecular Neurodegeneration |
| title | Disruption of the NF-κB/IκBα Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons |
| title_full | Disruption of the NF-κB/IκBα Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons |
| title_fullStr | Disruption of the NF-κB/IκBα Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons |
| title_full_unstemmed | Disruption of the NF-κB/IκBα Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons |
| title_short | Disruption of the NF-κB/IκBα Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons |
| title_sort | disruption of the nf κb iκbα autoinhibitory loop improves cognitive performance and promotes hyperexcitability of hippocampal neurons |
| url | http://www.molecularneurodegeneration.com/content/6/1/42 |
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