| First Author | Dresselhaus EC | Year | 2018 |
| Journal | J Neurosci | Volume | 38 |
| Issue | 17 | Pages | 4093-4103 |
| PubMed ID | 29555853 | Mgi Jnum | J:261198 |
| Mgi Id | MGI:6154418 | Doi | 10.1523/JNEUROSCI.2663-16.2018 |
| Citation | Dresselhaus EC, et al. (2018) Targeting of NF-kappaB to Dendritic Spines Is Required for Synaptic Signaling and Spine Development. J Neurosci 38(17):4093-4103 |
| abstractText | 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 kappaB (NF-kappaB), give rise to stimulus-appropriate neuronal responses remain unclear. We report that the p65/RelA subunit of NF-kappaB confers subcellular enrichment at neuronal dendritic spines and engineer a p65 mutant that lacks spine enrichment (p65DeltaSE) but retains inherent transcriptional activity equivalent to wild-type p65. Wild-type p65 or p65DeltaSE both rescue NF-kappaB-dependent gene expression in p65-deficient murine hippocampal neurons responding to diffuse (PMA/ionomycin) stimulation. In contrast, neurons lacking spine-enriched NF-kappaB are selectively impaired in NF-kappaB-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-kappaB-dependent growth of dendritic spines to test physiological function of spine-enriched NF-kappaB in an activity-dependent response. Expression of wild-type p65, but not p65DeltaSE, 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-kappaB 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, ensuring biologically appropriate responses, remain incompletely understood. NF-kappaB is a potent transcription factor with evolutionarily conserved functions in learning and the growth of excitatory synaptic contacts. Neuronal NF-kappaB is localized in both synapse and somatic compartments, but whether the synaptic pool of NF-kappaB has discrete functions is unknown. This study reveals that NF-kappaB enriched in dendritic spines (the postsynaptic sites of excitatory contacts) is selectively required for NF-kappaB 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. |
