Impaired Adult Neurogenesis Associated with Short-Term Memory Defects in NF-κB p50-Deficient Mice

Denis-Donini, S.; Dellarole, Anna; Crociara, Paola; Francese, Maria Teresa; Bortolotto, Valeria; Quadrato, Giorgia; Canonico, Pier Luigi; Orsetti, Marco; Ghi, Piera; Memo, Maurizio; Bonini, Sara Anna; Ferrari-Toninelli, Giulia; Grilli, Mariagrazia

doi:10.1523/jneurosci.0148-08.2008

Cited by 123 publications

(144 citation statements)

References 46 publications

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“…There is one report that RelA is expressed in NSCs in the SVZ, whereas p50 is expressed in migrating neural precursors (37). In p50 deletion mice, there is no effect on cell proliferation in adult hippocampus under nonstress conditions (38), consistent with the negative results of the current study. Additional studies of stress in p50 mutant mice, or in conditional deletion mutants, would further characterize the role of NF-κB family members.…”

Section: Discussionsupporting

confidence: 91%

Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior

Koo

Russo

Ferguson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

548

389

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Proinflammatory cytokines, such as IL-1β, have been implicated in the cellular and behavioral effects of stress and in mood disorders, although the downstream signaling pathways underlying these effects have not been determined. In the present study, we demonstrate a critical role for NF-κB signaling in the actions of IL-1β and stress. Stress inhibition of neurogenesis in the adult hippocampus, which has been implicated in the prodepressive effects of stress, is blocked by administration of an inhibitor of NF-κB. Further analysis reveals that stress activates NF-κB signaling and decreases proliferation of neural stem-like cells but not early neural progenitor cells in the adult hippocampus. We also find that depressive-like behaviors caused by exposure to chronic stress are mediated by NF-κB signaling. Together, these data identify NF-κB signaling as a critical mediator of the antineurogenic and behavioral actions of stress and suggest previously undescribed therapeutical targets for depression.M ood disorders represent a major health concern, affecting over 15% of the population in developed countries, resulting in enormous personal and economic costs and, in many cases, suicide (1, 2). Despite significant efforts, the neurobiological mechanisms underlying depression have not been characterized. Both genetic and environmental factors contribute to depression, and traumatic or repeated stress is known to precipitate or exacerbate mood disorders (3-5). In addition, proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, that are induced by injury and infection as well as by psychological stress have been implicated in depressive behavior in rodent models and depressed patients (6-8).Exposure to stress and depression can result in atrophy of limbic brain regions that control emotion and mood, including inhibition of neurogenesis in the adult hippocampus (5, 9, 10). Inhibition of neurogenesis is observed with many different types of physical and psychological stressors, but the types of cells, neural stem-like cells (NSCs) or intermediate transient amplifying neural progenitor cells (ANPs), that are influenced have not been characterized (9, 11). A role for proinflammatory cytokines is supported by a recent report that IL-1β signaling is necessary and sufficient for the antineurogenic and behavioral effects of stress (6). One possible signaling cascade that could mediate the effects of IL-1β is NF-κB, which is activated by IL-1β and other cytokines both in peripheral immune cells and in the brain (8,12). Chronic stress enhances the activation of NF-κB in response to inflammatory stimuli (13,14), and social stress increases NF-κB signaling in healthy subjects and produces an exaggerated response in depressed patients (15,16).In the present study, we investigate the role of NF-κB in the cellular and behavioral responses to acute and chronic stress. The results demonstrate that the inhibition of neurogenesis by stress occurs via activation of NF-κB in NSCs and that stress-induced anhedonia, a core symptom of depr...

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Section: Discussionsupporting

confidence: 91%

Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior

Koo

Russo

Ferguson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

548

389

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“…19 NF-kB signaling is involved in a wide range of biological processes, including inflammation, immunity, and synaptic plasticity, and it has also been suggested to regulate adult neurogenesis. 20 Clinically, most literature patients with TRAPPC9 mutations are described as affected by a nonsyndromic form of ID, although recurrent brain abnormalities and obesity were described in some of them. We made an extensive phenotypic analysis of our patients, …”

Section: Discussionmentioning

confidence: 99%

TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype

et al. 2012

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Intellectual disability (ID) with autosomal recessive (AR) inheritance is believed to be common; however, very little is known about causative genes and genotype-phenotype correlations. The broad genetic heterogeneity of AR-ID, and its usually nonsyndromic nature make it difficult to pool multiple pedigrees with the same underlying genetic defect to achieve consistent nosology. Nearly all autosomal genes responsible for recessive cognitive disorders have been identified in large consanguineous families from the Middle East, and nonsense mutations in TRAPPC9 have been reported in a total of 5. Although several recurrent phenotypic abnormalities are described in some of these patients, the associated phenotype is usually referred to as nonsyndromic. By means of single-nucleotide polymorphism-array first and then by exome sequencing, we identified a new pathogenic mutation in TRAPPC9 in two Italian sisters born to healthy and apparently nonconsanguineous parents. It consists of a homozygous splice site mutation causing exon skipping with frameshift and premature termination, as confirmed by mRNA sequencing. By detailed phenotypic analysis of our patients, and by critical literature review, we found that homozygous TRAPPC9 loss-of-function mutations cause a distinctive phenotype, characterized by peculiar facial appearance, obesity, hypotonia (all signs resembling a Prader-Willi-like phenotype), moderate-to-severe ID, and consistent brain abnormalities.

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“…p50 Ϫ/Ϫ mice have been extensively used in an attempt to clarify the role of NF-B in developing, adult, and aged nervous system. Indeed, this mouse model has been shown to display accelerated aging (Lu et al, 2006) and a dramatic impairment in hippocampal neurogenesis linked to a selective cognitive deficit in hippocampal-dependent spatial short-term memory (Denis-Donini et al, 2008). Mice lacking p50 subunit also display an increased exploratory activity and reduced anxiety behavior (Kassed and Herkenham, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Ϫ/Ϫ (B6;129P2-Nfkb 1tm 1 Bal/J; The Jackson Laboratory) and wild-type (wt) mice (B6;129PF2; The Jackson Laboratory) were maintained in high-efficiency particulate airfiltered THOREN units (THOREN Caging Systems) at the University of Piemonte Orientale animal facility, were kept three to four per cage, and had ad libitum access to food and water (Denis-Donini et al, 2008). Animal treatments were performed in accordance with the National Institutes of Health guidelines and approved by the local institutional animal care and use committee.…”

Section: Primary Cortical Neurons Cultures Nf-b P50mentioning

confidence: 99%

“…To gain insight into the role of NF-B in neuronal differentiation, we have taken advantage of the availability of mice carrying a homozygous deletion of the NF-B1 gene encoding the p50 subunit (Sha et al, 1995;Denis-Donini et al, 2008). Brain cortical neuroblasts were isolated from E15 wt and p50 Ϫ/Ϫ embryos.…”

Section: Neurite Branching and Varicosities Are Reduced In P50mentioning

confidence: 99%

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Nuclear Factor κB-Dependent Neurite Remodeling Is Mediated by Notch Pathway

Bonini¹,

Ferrari-Toninelli²,

Uberti³

et al. 2011

J. Neurosci.

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In this study, we evaluated whether a cross talk between nuclear factor B (NF-B) and Notch may take place and contribute to regulate cell morphology and/or neuronal network in primary cortical neurons. We found that lack of p50, either induced acutely by inhibiting p50 nuclear translocation or genetically in p50 Ϫ/Ϫ mice, results in cortical neurons characterized by reduced neurite branching, loss of varicosities, and Notch1 signaling hyperactivation. The neuronal morphological effects found in p50 Ϫ/Ϫ cortical cells were reversed after treatment with the ␥-secretase inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-1-alanyl 1]-S-phenylglycine t-butyl ester) or Notch RNA interference. Together, these data suggested that morphological abnormalities in p50 Ϫ/Ϫ cortical neurons were dependent on Notch pathway hyperactivation, with Notch ligand Jagged1 being a major player in mediating such effect. In this line, we demonstrated that the p50 subunit acts as transcriptional repressor of Jagged1. We also found altered distribution of Notch1 and Jagged1 immunoreactivity in the cortex of p50 Ϫ/Ϫ mice compared with wild-type littermates at postnatal day 1. These data suggest the relevance of future studies on the role of Notch/NF-B cross talk in regulating cortex structural plasticity in physiological and pathological conditions.

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Impaired Adult Neurogenesis Associated with Short-Term Memory Defects in NF-κB p50-Deficient Mice

Cited by 123 publications

References 46 publications

Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior

Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior

TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype

Nuclear Factor κB-Dependent Neurite Remodeling Is Mediated by Notch Pathway

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