Long-term forms of brain plasticity share a requirement for changes in gene expression induced by neuronal activity. Mechanisms that determine how the distinct and overlapping functions of multiple activity-responsive transcription factors, including nuclear factor kappa B (NF-κB), give rise to stimulus-appropriate neuronal responses remain unclear. We report that the p65/RelA subunit of NF-κB confers subcellular enrichment at neuronal dendritic spines and engineer a p65 mutant that lacks spine-enrichment (ΔSEp65) but retains inherent transcriptional activity equivalent to wild-type p65. Wild-type p65 or ΔSEp65 both rescue NF-κB-dependent gene expression in p65-deficient murine hippocampal neurons responding to diffuse (PMA/ionomycin) stimulation. In contrast, neurons lacking spine-enriched NF-κB are selectively impaired in NF-κB-dependent gene expression induced by elevated excitatory synaptic stimulation (bicuculline or glycine). We used the setting of excitatory synaptic activity during development that produces NF-κB-dependent growth of dendritic spines to test physiological function of spine-enriched NF-κB in an activity-dependent response. Expression of wild-type p65, but not ΔSEp65, is capable of rescuing spine density to normal levels in p65-deficient pyramidal neurons. Collectively, these data reveal that spatial localization in dendritic spines contributes unique capacities to the NF-κB transcription factor in synaptic activity-dependent responses. SIGNIFICANCE STATEMENT Extensive research has established a model in which the regulation of neuronal gene expression enables enduring forms of plasticity and learning. However, mechanisms imparting stimulus-specificity to gene regulation, insuring biologically appropriate responses, remain incompletely understood. NF-κB is a potent transcription factor with evolutionarily-conserved functions in learning and the growth of excitatory synaptic contacts. Neuronal NF-κB is localized in both synapse and somatic compartments, but whether the synaptic pool of NF-κB has discrete functions is unknown. This study reveals that NF-κB enriched in dendritic spines (the postsynaptic sites of excitatory contacts) is selectively required for NF-κB activation by synaptic stimulation and normal dendritic spine development. These results support spatial localization at synapses as a key variable mediating selective stimulus-response coupling.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
- Immunology and Microbiology(all)
- Pharmacology, Toxicology and Pharmaceutics(all)