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

Abstract

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

Minimal NF-κB activity in neurons

“…Based on the extensive literature on neuronal NF-κB activation, we tested the most-studied candidates. Supported by published data (Tamatani et al, 1999, Albensi and Mattson, 2000, Marchetti et al, 2004, Manuvakhova et al, 2011, Shim et al, 2011), the strongest and most consistent activator of NF-κB in neurons was TNFα. We employed multiple assays to demonstrate the response dynamics, and we compared the magnitude of the neuronal response to that in mixed brain cells.…”

IκB Kinase/Nuclear Factor κB-Dependent Insulin-Like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling

“…Therefore, loss of SAP97␤ may be one molecular reason for synaptic reduction of GluA1, thus contributing to reduced AMPAR-mediated basal synaptic transmission. Interestingly, a gainof-function mouse model for NF-B activation exhibited the reverse effect of increased neuronal excitatory network activity and synchrony (Shim et al, 2011). In both mouse models, hippocampal LTP remained intact, indicating a homosynaptic scaling of AMPAR responses mediated by IKK/NF-B signaling.…”

Transcriptional and epigenetic regulation of Hebbian and non-Hebbian plasticity

“…Other potential candidates include nuclear factor-κB (NF-κB) as it too is known to associate with epigenome-modifying complexes (Chen et al, 2011; Lanzillotta et al, 2010). In fact, hippocampal neurons from mice with mutations in the IκBα promoter, the primary inhibitor of NF-κB, exhibit spontaneous burst firing and hyperexcitability (Shim et al, 2011) that could be explained via modulation of voltage-dependent calcium channels and ionotropic glutamate receptor channels (Furukawa and Mattson, 2002). Finally, do genetic or pharmacological manipulations of epigenetic enzymes modulate neuronal intrinsic excitability?…”