Plasticity at synapses is a fundamental process believed to underlie the remarkable ability of our brains to adapt to changing environments and new challenges. It is involved in neural development, learning and memory, and response to injury, as well as accompanying the apoptotic process common to many neurodegenerative diseases. Synaptic remodeling, the process of changing the size, shape, number or connectivity of synapses, occurs during plasticity and is thought to be a critical mechanism regulating synaptic function. In the mammalian brain, the majority of excitatory synapses occur on dendritic protrusions termed spines. This research proposal will investigate how the nuclear factor kappa B (NF-:B) transcription factor may function to regulate synaptic contacts received by hippocampal neurons. Interestingly, NF-:B is itself located at synapses and can be activated by excitatory activity. These investigations will explore the relationship between pathways of synaptic remodeling and NF-:B activation, and the resulting changes in gene expression which may augment dendritic spines and postsynaptic responses. The hippocampus has been selected as a model system for studying the effects of neuronal NF-:B on dendritic spine and synapse number because it is a well-defined area of both physiological (learning and memory) as well as pathological (stroke, Alzheimer's disease) neuronal function. The studies will use hippocampal tissue from both adult mice and neonates, including transgenic mice. Specifically, experiments will focus on how the NF-:B transcription factor may be recruited to or tethered in dendritic spines, the pathway of NF-:B activation at synapses, and the regulation of dendritic spine density and morphology by NF-:B with potential functional effects on synaptic physiology.

Public Health Relevance

The knowledge gained from this research will create a better understanding of the endogenous signaling cascades responsible for transcription factor modulation of synapse formation and synaptic remodeling. These processes are of fundamental neurological consequence for brain plasticity and repair and are hypothesized to be a structural basis underlying learning and memory. In addition, it is the aim of these investigations to shed light on how pathways of synaptic remodeling, like the NF-?B transcription factor itself, could operate in both normal brain function as well as in neurological disorders and to provide potential targets for diagnosing and treating brain disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH080740-05
Application #
8220924
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Asanuma, Chiiko
Project Start
2008-05-06
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$328,779
Indirect Cost
$128,304
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Boersma, Matthew C H; Dresselhaus, Erica C; De Biase, Lindsay M et al. (2011) A requirement for nuclear factor-kappaB in developmental and plasticity-associated synaptogenesis. J Neurosci 31:5414-25
Shrum, Cynthia K; Defrancisco, Daniel; Meffert, Mollie K (2009) Stimulated nuclear translocation of NF-kappaB and shuttling differentially depend on dynein and the dynactin complex. Proc Natl Acad Sci U S A 106:2647-52