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A requirement for nuclear factor-kappaB 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 nuclear factor-?B (NF-?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-?B activity is elevated by excitatory transmission during periods of rapid spine and synapse development. During in vitro synaptogenesis, NF-?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-?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-?B similarly reduces spine density and also diminishes the amplitude of synaptic responses. In contrast, after developmental synaptogenesis has plateaued, endogenous NF-?B activity is low and p65 deficiency no longer attenuates basal spine density. Instead, NF-?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-?B on spine density require transcription and the NF-?B-dependent regulation of PSD-95, a critical postsynaptic component. Collectively, our data define a distinct role for NF-?B in imparting transcriptional regulation required for the induction of changes to, but not maintenance of, excitatory synapse and spine density.

SUBMITTER: Boersma MC

PROVIDER: S-EPMC3113725 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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A requirement for nuclear factor-kappaB in developmental and plasticity-associated synaptogenesis.

Boersma Matthew C H MC Dresselhaus Erica C EC De Biase Lindsay M LM Mihalas Anca B AB Bergles Dwight E DE Meffert Mollie K MK

The Journal of neuroscience : the official journal of the Society for Neuroscience 20110401 14

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-κB (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 s ...[more]

PMID: 21471377

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Project description:BackgroundCardiac remodeling is generally an adverse sign and is associated with heart failure (HF) progression. NFkB, an important transcription factor involved in many cell survival pathways, has been implicated in the remodeling process, but its role in the heart is still controversial. Recently, a promoter polymorphism associated with a lesser activation of the NFKB1 gene was also associated with Dilated Cardiomyopathy. The purpose of this study was to evaluate the association of this polymorphism with clinical and functional characteristics of heart failure patients of different etiologies.MethodsA total of 493 patients with HF and 916 individuals from a cohort of individuals from the general population were investigated. The NFKB1 -94 insertion/deletion ATTG polymorphism was genotyped by High Resolution Melt discrimination. Allele and genotype frequencies were compared between groups. In addition, frequencies or mean values of different phenotypes associated with cardiovascular disease were compared between genotype groups. Finally, patients were prospectively followed-up for death incidence and genotypes for the polymorphism were compared regarding disease onset and mortality incidence in HF patients.ResultsWe did not find differences in genotype and allelic frequencies between cases and controls. Interestingly, we found an association between the ATTG1/ATTG1 genotype with right ventricle diameter (P = 0.001), left ventricle diastolic diameter (P = 0.04), and ejection fraction (EF) (P = 0.016), being the genotype ATTG1/ATTG1 more frequent in patients with EF lower than 50% (P = 0.01). Finally, we observed a significantly earlier disease onset in ATTG1/ATTG1 carriers.ConclusionThere is no genotype or allelic association between the studied polymorphism and the occurrence of HF in the tested population. However, our data suggest that a diminished activation of NFKB1, previously associated with the ATTG1/ATTG1 genotype, may act modulating on the onset of disease and, once the individual has HF, the genotype may modulate disease severity by increasing cardiac remodeling and function deterioration.

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A requirement for nuclear factor-kappaB in developmental and plasticity-associated synaptogenesis.

Publications

A requirement for nuclear factor-kappaB in developmental and plasticity-associated synaptogenesis.

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