| Summary: | <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>
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