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

Abstract

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 NF-κB transcription factor, which is required for learning and memory, controls excitatory synapse and dendritic spine formation and morphology in murine hippocampal neurons. Endogenous NF-κB activity is elevated by excitatory transmission during periods of rapid spine and synapse development. During in-vitro synaptogenesis, NF-κB enhances dendritic spine and excitatory synapse density and loss of endogenous p65 decreases spine density and spine head volume. Cell-autonomous function of NF-κB within the postsynaptic neuron is sufficient to regulate the formation of both pre- and post-synaptic elements. During synapse development in-vivo, loss of NF-κB similarly reduces spine density and also diminishes the amplitude of synaptic responses. In contrast, after developmental synaptogenesis has plateaued, endogenous NF-κB activity is low and p65-deficiency no longer attenuates basal spine density. Instead, NF-κB 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-κB on spine density require transcription and the NF-κB-dependent regulation of PSD-95, a critical postsynaptic component. Collectively, our data define a distinct role for NF-κB in imparting transcriptional regulation required for the induction of changes to, but not maintenance of, excitatory synapse and spine density.

IκB Kinase/Nuclear Factor κB-Dependent Insulin-Like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling

“…1 B). Recent studies implied that spinogenesis of medium spiny GABAergic neurons in the nucleus accumbens depends on IKK2 activity, while RelA function was shown to control synaptogenesis in the developing hippocampus (Russo et al, 2009;Boersma et al, 2011). Our biochemical data show that IKK activation takes place directly at the PSD under basal conditions in adult mice.…”

“…IKK/NF-B signaling has recently been shown to promote the development and remodeling of synaptic connections (Russo et al, 2009;Boersma et al, 2011;Christoffel et al, 2011). However, NF-B-dependent mechanisms and target genes that mediate the structural changes finally resulting in formation, maturation, and stabilization of synapses, were hitherto poorly characterized.…”

“…It was unclear whether IKK-dependent regulation of spine density is restricted to a distinct developmental time window (Boersma et al, 2011) or whether it is extending into adulthood. We therefore used a different transgenic mouse model (Camk2a-tTA ϫ IKK2-DN), named IKK2 nDN , which allows the expression of a dominant-negative allele of the Ikbkb gene (IKK2-DN, N-terminally VSV-tagged) in forebrain neurons in a doxycycline (DOX)-dependent manner (Herrmann et al, 2005;Baumann et al, 2007).…”

“…Recent studies provide evidence that IKK/NF-B signaling is directly involved in spinogenesis and synapse formation (Russo et al, 2009;Boersma et al, 2011;Christoffel et al, 2011). To unravel underlying molecular mechanisms, we used mouse models with either a conditional expression of a dominant-negative acting IKK2 allele or a specific deletion of IKK2 in excitatory neurons.…”

Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior

“…Similar to our findings, overexpression of the NFkB transcriptional complex subunit p65 in cultured hippocampal pyramidal neurons results in increased spine density. Conversely, knockout of the p65 gene in a transgenic line leads to decreased spine density in vivo (Boersma et al, 2011). IkK activity in the hippocampus has also been found to affect histone acteylation, and this action was shown to be a critical regulator of reconsolidation of conditioned fear memories (Lubin and Sweatt, 2007).…”