TY - JOUR
T1 - Disruption of the NF-κB/IκBα autoinhibitory loop improves cognitive performance and promotes hyperexcitability of hippocampal neurons
AU - Shim, David J.
AU - Yang, Li
AU - Reed, J. Graham
AU - Noebels, Jeffrey L.
AU - Chiao, Paul J.
AU - Zheng, Hui
N1 - Funding Information:
We are grateful to N. Aithmitti and X. Chen for expert technical support, Z. Wang and B. Peng for assistance with initial breeding and characterization of the mice, and N. Justice and members of the Zheng laboratory for constructive discussions and help with the manuscript. We thank C. Spencer and the Baylor College of Medicine IDDRC Administrative, Mouse Neurobehavior, and Mouse Physiology cores (HD24064) for their assistance. This work was supported by grants from NIH (AG20670, AG32051, and AG33467 to HZ; NS614283 to DS).
PY - 2011
Y1 - 2011
N2 - 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 (IκBα M/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 IκBα M/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 IB autoinhibitory loop is critical for titrating appropriate levels of endogenous NF-κB activity to maintain proper neuronal function.
AB - 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 (IκBα M/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 IκBα M/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 IB autoinhibitory loop is critical for titrating appropriate levels of endogenous NF-κB activity to maintain proper neuronal function.
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U2 - 10.1186/1750-1326-6-42
DO - 10.1186/1750-1326-6-42
M3 - Article
C2 - 21663635
AN - SCOPUS:80955125227
SN - 1750-1326
VL - 6
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 42
ER -