title: Disruption of the NF-κB/IκBα Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons.
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.
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. huiz@bcm.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Shim
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: J Graham
authors.initials: JG
authors.lastname: Reed
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng