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Roles for NF-κB and Gene Targets of NF-κB in Synaptic Plasticity, Memory, and Navigation

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Abstract

Although traditionally associated with immune function, the transcription factor nuclear factor kappa B (NF-κB) has garnered much attention in recent years as an important regulator of memory. Specifically, research has found that NF-κB, localized in both neurons and glia, is activated during the induction of long-term potentiation (LTP), a paradigm of synaptic plasticity and correlate of memory. Further, experimental manipulation of NF-κB activation or its blockade results in altered memory and spatial navigation abilities. Genetic knockout of specific NF-κB subunits in mice results in memory alterations. Collectively, such data suggest that NF-κB may be a requirement for memory, although the direction of the response (i.e., memory enhancement or deficit) is inconsistent. A limited number of gene targets of NF-κB have been recently identified in neurons, including neurotrophic factors, calcium-regulating proteins, other transcription factors, and molecules associated with neuronal outgrowth and remodeling. In turn, several key molecules are activators of NF-κB, including protein kinase C and [Ca++]i. Thus, NF-κB signaling is complex and under the regulation of numerous proteins involved in activity-dependent synaptic plasticity. The purpose of this review is to highlight the literature detailing a role for NF-κB in synaptic plasticity, memory, and spatial navigation. Secondly, this review will synthesize the research evaluating gene targets of NF-κB in synaptic plasticity and memory. Although there is ample evidence to suggest a critical role for NF-κB in memory, our understanding of its gene targets in neurons is limited and only beginning to be appreciated.

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Abbreviations

NF-κB:

Nuclear factor kappa B

LTP:

Long-term potentiation

CREB:

cAMP response element-binding protein

AP-1:

Activating protein 1

(C/EBP):

CCAAT enhancer binding protein

EGR:

Early growth response factor

IKK:

IκB kinase

TNFα:

Tumor necrosis factor alpha

BDNF:

Brain-derived neurotrophic factor

NCAM:

Neural cell adhesion molecule

APP:

Amyloid precursor protein

ROS:

Reactive oxygen species

IEG:

Immediate early genes

LTD:

Long-term depression

PKA:

Protein kinase A

PKC:

Protein kinase C

(CaMKII):

Calcium-calmodulin kinase II

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

NMDA:

N-methyl-d-aspartic acid

CBP:

CREB binding protein

KO:

Knockout

8-RAM:

Radial arm maze

TMT:

Trimethyltin

MWM:

Morris water maze

PI3-K:

Phosphatidyl inositol 3-kinase

MEK:

Mitogen-activated protein kinase kinase

p38-MAPK:

p38-mitogen-activated protein kinase

DHPG:

(S)-3,5-dihydroxyphenylglycine

mGluR:

Metabotropic glutamate receptor

GABA:

Gamma-aminobutyric acid

IκBα-SR:

IκBα superrepressor

GAD 65:

Glutamate decarboxylase 65

NFAT:

Nuclear factor of activated T cells

MnSOD:

Manganese superoxide dismutase

ER:

Endoplasmic reticulum

VDCC:

Voltage-dependent calcium channel

NOS:

Nitric oxide synthase

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Acknowledgments

This work was funded by the National Sciences and Engineering Research Council (in separate grants to B.C.A. and D.M.K.). Dr. Ben Albensi is a Research Affiliate at the University of Manitoba’s Centre on Aging and holds the Honourable Douglas Everett, Patricia Everett and the Royal Canadian Properties Endowment Fund Chair. Dr. Debbie Kelly holds a Canada Research Chair in Comparative Cognition.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Neurodegenerative Disorders, St. Boniface Research Centre, R4050 351 Tache Avenue, Winnipeg, MB, Canada, R2H 2A6

    Wanda M. Snow & Benedict C. Albensi

  2. Department of Pharmacology and Therapeutics, University of Manitoba, A203 Chown Bldg., 753 McDermot Avenue, Winnipeg, MB, Canada, R3E 0T6

    Wanda M. Snow & Benedict C. Albensi

  3. Department of Psychology, University of Manitoba, 190 Dysart Rd, Winnipeg, MB, Canada, R3T 2N2

    Brenda M. Stoesz & Debbie M. Kelly

  4. Department of Electrical & Computer Engineering, Faculty of Engineering, E2-290 Engineering & Information Technology Complex, University of Manitoba, Winnipeg, MB, Canada, R3T 2N2

    Benedict C. Albensi

  5. Manitoba Institute of Child Health, 513-715 McDermot Avenue, Winnipeg, MB, Canada, R3E 3P4

    Benedict C. Albensi

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  1. Wanda M. Snow
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  2. Brenda M. Stoesz
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  4. Benedict C. Albensi
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Correspondence to Benedict C. Albensi.

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Snow, W.M., Stoesz, B.M., Kelly, D.M. et al. Roles for NF-κB and Gene Targets of NF-κB in Synaptic Plasticity, Memory, and Navigation. Mol Neurobiol 49, 757–770 (2014). https://doi.org/10.1007/s12035-013-8555-y

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  • DOI: https://doi.org/10.1007/s12035-013-8555-y

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