A Requirement for Nuclear Factor-κB in Developmental and Plasticity-Associated Synaptogenesis

Structural plasticity of dendritic spines and synapses is a fundamental mechanism governing neuronal circuits and may form an enduring basis for information storage in the brain. We find that the p65 subunit of the nuclear factor-kappa B (NF-kappa B) transcription factor, which is required for learning and memory, controls excitatory synapse and dendritic spine formation and morphology in murine hippocampal neurons. Endogenous NF-kappa B activity is elevated by excitatory transmission during periods of rapid spine and synapse development. During in vitro synaptogenesis, NF-kappa B enhances dendritic spine and excitatory synapse density and loss of endogenous p65 decreases spine density and spine head volume. Cell-autonomous function of NF-kappa B within the postsynaptic neuron is sufficient to regulate the formation of both presynaptic and postsynaptic elements. During synapse development in vivo, loss of NF-kappa B similarly reduces spine density and also diminishes the amplitude of synaptic responses. In contrast, after developmental synaptogenesis has plateaued, endogenous NF-kappa B activity is low and p65 deficiency no longer attenuates basal spine density. Instead, NF-kappa B in mature neurons is activated by stimuli that induce demand for new synapses, including estrogen and short-term bicuculline, and is essential for upregulating spine density in response to these stimuli. p65 is enriched in dendritic spines making local protein-protein interactions possible; however, the effects of NF-kappa B on spine density require transcription and the NF-kappa B-dependent regulation of PSD-95, a critical postsynaptic component. Collectively, our data define a distinct role for NF-kappa B in imparting transcriptional regulation required for the induction of changes to, but not maintenance of, excitatory synapse and spine density.