The nuclear factor-kappaB (NF-kB) family of transcription factors is expressed in nearly all cell types and regulates the transcriptional response to a diverse and growing list of stimuli. In the central nervous system (CMS), NF-kB has been implicated in many pathologic states including ischemia, inflammation, and neurodegeneration. Recent studies, however, have demonstrated a clear role for NF-kB in normal development and function of the brain. Loss of NF-kB activity, for example, results in deficits in LTP and long-term memory formation. In fact, NF-kB is constitutively activated in various brain regions including cortex and hippocampus, likely due to ongoing synaptic transmission throughout neuronal networks. Normally, NF-kB is regulated by the kB family of inhibitory proteins, especially kBa. Consensus KB binding sites have been discovered in the kBa promoter and its expression is indeed induced upon NF-kB activation, thus forming an important autoregulatory loop. This loop is highly conserved across species, implying a critical need for precise regulation of NF-kB. To test the role of NF-kB regulation in maintaining optimal neuronal function, I have genetically disrupted the kBa autoregulatory loop by generating knock-in mice with specific mutations of the kB sites in the kBa promoter. My preliminary studies have shown that disruption of the kBa autoregulatory loop results in misregulation of NF-kB activity in the brain. Furthermore, these mice have reduced expression of the AMPAR subunit GluR1 in the hippocampus and a deficit in LTP induction. Based on these findings, I hypothesize that misregulation of NF-kB leads to direct repression of GluR1 transcription and results in impaired neuronal function and plasticity. This hypothesis will be tested with the following specific aims: 1. Determine if misregulation of NF-kB directly represses the transcription of GluR1, 2. Define the role of the kBa autoregulatory loop in synaptic transmission and plasticity, and 3. Determine if normalization of NF-kB regulation rescues the GluR1 and LTP deficits. The experiments in this proposal will allow us to better understand the role of NF-kB regulation in synaptic transmission and plasticity.
These results will not only provide insight into the molecular mechanisms underlying learning and memory, but will also suggest possible new therapeutic strategies for diseases of cognition such as Alzheimer's disease.
| Lian, Hong; Shim, David J; Gaddam, Samson S K et al. (2012) I?B? deficiency in brain leads to elevated basal neuroinflammation and attenuated response following traumatic brain injury: implications for functional recovery. Mol Neurodegener 7:47 |
| Shim, David J; Yang, Li; Reed, J Graham et al. (2011) Disruption of the NF-?B/I?B? Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons. Mol Neurodegener 6:42 |
