Targeting of NF-κB to Dendritic Spines is Required for Synaptic Signaling and Spine Development

Abstract

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-{kappa}B), give rise to stimulus-appropriate neuronal responses remain unclear. We report that the p65/RelA subunit of NF-{kappa}B confers subcellular enrichment at neuronal dendritic spines and engineer a p65 mutant that lacks spine-enrichment ({Delta}SEp65) but retains inherent transcriptional activity equivalent to wild-type p65. Wild-type p65 or {Delta}SEp65 both rescue NF-{kappa}B-dependent gene expression in p65-deficient murine hippocampal neurons responding to diffuse (PMA/ionomycin) stimulation. In contrast, neurons lacking spine-enriched NF-{kappa}B are selectively impaired in NF-{kappa}B-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-{kappa}B-dependent growth of dendritic spines to test physiological function of spine-enriched NF-{kappa}B in an activity-dependent response. Expression of wild-type p65, but not {Delta}SEp65, 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-{kappa}B transcription factor in synaptic activity-dependent responses.\n\nSIGNIFICANCE STATEMENTExtensive 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-{kappa}B is a potent transcription factor with evolutionarily-conserved functions in learning and the growth of excitatory synaptic contacts. Neuronal NF-{kappa}B is localized in both synapse and somatic compartments, but whether the synaptic pool of NF-{kappa}B has discrete functions is unknown. This study reveals that NF-{kappa}B enriched in dendritic spines (the postsynaptic sites of excitatory contacts) is selectively required for NF-{kappa}B 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.