Much of what we know, or suspect we know, about learning and memory comes from the study of long-term potentiation (LTP). LTP, first discovered in the hippocampus, is an increase in the strength or weight of synapses that can be induced by strong high frequency trains of action potentials. Despite years of study, it is still not known precisely how action potentials arriving al synapses in particular temporal patterns can generate cellular signals that trigger the biochemical reactions within dendritic spines that lead to long-term modifications of synaptic strength. This project will provide an understanding of this process by combining modeling and experimental studies to characterize the cellular signaling processes that occur with the development of long-term potentiation.
Specific aims are: 1) To quantify how much of a change at individual synapses is necessary to account for the amount of potentiation observed in LTP, 2) To determine systematically stimulation protocols that are successful in eliciting LTP to allow identification of signaling cascades that particular protocols may activate, 3) To characterize the role of synaptic failures in initiating or hindering signaling processes, 4) To identify the differences in signaling mechanisms involved in NMDA-dependent and NMDA-independent forms of LTP in hippocampal area CA1, 5) To understand how molecular signaling complexes develop and function in dendritic spines. The combined modeling and experimental studies will provide critical insights into some of the outstanding questions about the mechanisms of cellular signaling in long-term potentiation. This knowledge can be used to understand mechanisms involved both in normal learning and memory and in the prevention or disruption of learning and memory that occurs with alcohol abuse. The methods used could have general applicability to signaling systems in other areas of physiology or for gene regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA014294-01
Application #
6641902
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (50))
Program Officer
Sorensen, Roger
Project Start
2002-09-30
Project End
2007-08-31
Budget Start
2002-09-30
Budget End
2003-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$217,747
Indirect Cost
Name
Ohio University Athens
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Athens
State
OH
Country
United States
Zip Code
45701
Owen, Benjamin; Grover, Lawrence M (2015) Activity-dependent differences in function between proximal and distal Schaffer collaterals. J Neurophysiol 113:3646-62
Kim, Eunyoung; Owen, Benjamin; Holmes, William R et al. (2012) Decreased afferent excitability contributes to synaptic depression during high-frequency stimulation in hippocampal area CA1. J Neurophysiol 108:1965-76
Zeng, Shangyou; Holmes, William R (2010) The effect of noise on CaMKII activation in a dendritic spine during LTP induction. J Neurophysiol 103:1798-808
Grover, Lawrence M; Kim, Eunyoung; Cooke, Jennifer D et al. (2009) LTP in hippocampal area CA1 is induced by burst stimulation over a broad frequency range centered around delta. Learn Mem 16:69-81
Ambros-Ingerson, Jose; Grover, Lawrence M; Holmes, William R (2008) A classification method to distinguish cell-specific responses elicited by current pulses in hippocampal CA1 pyramidal cells. Neural Comput 20:1512-36
Holmes, William R; Grover, Lawrence M (2006) Quantifying the magnitude of changes in synaptic level parameters with long-term potentiation. J Neurophysiol 96:1478-91
Holmes, W R; Ambros-Ingerson, J; Grover, L M (2006) Fitting experimental data to models that use morphological data from public databases. J Comput Neurosci 20:349-65
Ambros-Ingerson, Jose; Holmes, William R (2005) Analysis and comparison of morphological reconstructions of hippocampal field CA1 pyramidal cells. Hippocampus 15:302-15