Dendritic spines are small morphologically identifiable structures that are the major sites where excitatory neurotransmission occurs in the mammalian brain. Thorough knowledge of their structure and function are critical for understanding information processing in the nervous system at the cellular level. Spines are well isolated biochemical compartments permitting each spine to function as an independent biochemical unit. Spines are also the site where synaptic plasticity is in part induced and maintained via the activation of well-orchestrated sets of enzymes that modify synaptic function. Critical in most models of synaptic plasticity is the role of increased intracellular Ca2+ in inducing long-term functional changes and spines have evolved unique mechanisms to finely control the temporal and quantitative nature of the Ca2+-signal. However, how this single second messenger is used to produce responses as distinct as long-term potentiation or long-term depression is not clear. We propose that calmodulin serves a critical role in determining how Ca2+ signals are decoded by the spine's biochemical apparatus. More specifically, we hypothesize that previously unrecognized Ca2+-dependent and Ca2+- independent calmodulin-target interaction are responsible for decoding the Ca2+-signal. We propose to test these ideas by applying a computational strategy.
Three specific aims will be accomplished. First, detailed models will be constructed of the Ca2+/calmodulin signaling pathway based on biophysical and enzymatic data collected from in vitro experiments. This will allow us to investigate an important role of calmodulin-target interaction in decoding Ca2+ signals in a well-mixed compartment. Second, a Monte Carlo computer simulation will be constructed to model molecular interaction between CaM and target protein that are undergoing diffusion in a non-homogenous model of spine cytoplasm. This novel simulation is based on and guided by on-going in vitro as well as in vivo fluorescence spectroscopic data of calmodulin-target protein interactions. Third, the simulation will be extended to incorporate geometric boundaries and spatial constraints of the dendritic spine. This model will allow us to explore how Ca2+- signal driven calmodulin-target interactions in the spine are orchestrated in space and time and to correlate their activation with different forms of synaptic plasticity (e.g., spike-timing dependent plasticity, LTP and LTD). The long-term goal of the studies is to establish a computational model of a spine that can be used to investigate hypotheses concerning the information processing capabilities of enzymatic networks constrained by known structural, biochemical and biophysical data.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center Houston
United States
Zip Code
Liao, Hsi-Wen; Ren, Xiaozhi; Peterson, Beth B et al. (2016) Melanopsin-expressing ganglion cells on macaque and human retinas form two morphologically distinct populations. J Comp Neurol 524:2845-72
Monaco, Joseph D; Rao, Geeta; Roth, Eric D et al. (2014) Attentive scanning behavior drives one-trial potentiation of hippocampal place fields. Nat Neurosci 17:725-31
Zhang, Yili; Liu, Rong-Yu; Heberton, George A et al. (2012) Computational design of enhanced learning protocols. Nat Neurosci 15:294-7
Byrne, Michael J; Waxham, M Neal; Kubota, Yoshihisa (2011) The impacts of geometry and binding on CaMKII diffusion and retention in dendritic spines. J Comput Neurosci 31:1-12
Aslam, Naveed; Zaheer, Irum (2011) The biosynthesis characteristics of TTP and TNF can be regulated through a posttranscriptional molecular loop. J Biol Chem 286:3767-76
Monaco, Joseph D; Abbott, L F; Abbott, Larry F (2011) Modular realignment of entorhinal grid cell activity as a basis for hippocampal remapping. J Neurosci 31:9414-25
Gavornik, Jeffrey P; Shouval, Harel Z (2011) A network of spiking neurons that can represent interval timing: mean field analysis. J Comput Neurosci 30:501-13
Mozzachiodi, Riccardo; Byrne, John H (2010) More than synaptic plasticity: role of nonsynaptic plasticity in learning and memory. Trends Neurosci 33:17-26
Xiong, Liang-Wen; Kleerekoper, Quinn K; Wang, Xu et al. (2010) Intra- and interdomain effects due to mutation of calcium-binding sites in calmodulin. J Biol Chem 285:8094-103
Kubota, Yoshihisa; Waxham, M Neal (2010) Lobe specific Ca2+-calmodulin nano-domain in neuronal spines: a single molecule level analysis. PLoS Comput Biol 6:e1000987

Showing the most recent 10 out of 62 publications