D Bray

DS Banks

Fidel Santamaria

Horace Deans

J Stiles

K Tanaka

NA Chebotareva

TA Ryan

Springer - Publisher Connector

POSTER PRESENTATION Open Access
Modeling the effects of molecular crowding on
cerebellar long term depression
Horace Deans, Fidel Santamaria*
From Twenty First Annual Computational Neuroscience Meeting: CNS*2012
Decatur, GA, USA. 21-26 July 2012
We built a Monte Carlo simulation to study the effects of
synaptic content on the expression of long term depression
(LTD), a form of synaptic plasticity, in the parallel fiber to
Purkinje cell synapse in the cerebellum. LTD is quantified
by the reduction in the number of a type of glutamate
receptor (AMPAR) in the synapse. Using MCell [1], we
modeled the intracellular volume and plasma membrane of
a single Purkinje cell dendritic spine. The model tracked
the position and biochemical state of all molecules involved
in cerebellar LTD after the release of calcium ions (Ca2+).
Since our model was based on a previously developed well-
mixed mass-action model [2], we had to obtain or derive
the diffusion coefficients of all molecules under their differ-
ent biochemical states. When we implemented the Monte
Carlo model with the known biophysical properties of
molecules, such as translocation and binding, the expres-
sion of LTD showed a smooth sigmoidal dependence on
the number of released Ca2+ which was not observed
experimentally. We then implemented the presence of
large concentrations of non-reactive macromolecules, a
condition known as molecular crowding [3,4]. The non-
reactive molecules were modeled using spheres of different
sizes either placed regularly or randomly throughout the
intracellular space of the spine. A classical approach would
suggest that the presence of these macromolecules would
result in an increase in the amount of Ca2+ needed to
induce LTD, producing a rightward shift of the curve.
Instead, our simulations show that the steepness of the sig-
moidal curve increased, replicating experimental results.
We further studied the effect of molecular crowding
on the efficiency of LTD expression. In the control
simulation we varied the diffusion coefficient of PKC
until no synaptic plasticity was induced. PKC is a key
protein in the expression of LTD that phosphorylates
AMPARs. We then ran the simulations with increasing
presence of crowding molecules. Interestingly, it was at
a crowding value of 45% that LTD was not only recov-
ered, but was 30% stronger. Molecular crowding in
other cell types has been calculated to be in the order of
40-45 % [5]. Furthermore, theoretical work suggests that
molecular crowding could be a mechanism to increase
the efficiency of biochemical reactions [6].
In summary, our results show that there is a strong
influence of molecular crowding in the activation of bio-
chemical signals in synapses. Based on our simulations
we propose that the regulation of crowding molecules in
spines could be a mechanism to control the reliability
and strength of synaptic plasticity.
Acknowledgements
Funding and resources provided by NSF HDR-093239, NSF EF-1137897 and
NIH-RCMI 2G12RR013646.
Published: 16 July 2012
References
1. Stiles J, Bartol TM: Monte Carlo methods for simulating realistic synaptic
microphysiology using MCell. In Computatinal neuroscience. Boca Raton:
CRC;De Schutter E 2000:.
2. Tanaka K, Khiroug L, Santamaria F, Doi T, Ogasawara H, Ellis-Davies GC,
Kawato M, Augustine GJ: Ca2+ requirements for cerebellar long-term
synaptic depression: role for a postsynaptic leaky integrator. Neuron
2007, 54(5):787-800.
3. Ryan TA, Myers J, Holowka D, Baird B, Webb WW: Molecular crowding on
the cell surface. Science 1988, 239(4835):61-64.
4. Bray D: SIGNALING COMPLEXES:Biophysical Constraints on Intracellular
Communication. Annual Review of Biophysics and Biomolecular Structure
1998, 27(1):59-75.
5. Banks DS, Fradin C: Anomalous diffusion of proteins due to molecular
crowding. Biophysical Journal 2005, 89(5):2960-2971.
6. Chebotareva NA, Kurganov BI, Livanova NB: Biochemical effects of
molecular crowding. Biochemistry (Mosc) 2004, 69(11):1239-1251.
doi:10.1186/1471-2202-13-S1-P47
Cite this article as: Deans and Santamaria: Modeling the effects of
molecular crowding on cerebellar long term depression. BMC
Neuroscience 2012 13(Suppl 1):P47.
* Correspondence: fidel.santamaria@utsa.edu
Department of Biology, The University of Texas at San Antonio, San Antonio,
TX 78249, USA
Deans and Santamaria BMC Neuroscience 2012, 13(Suppl 1):P47
http://www.biomedcentral.com/1471-2202/13/S1/P47
© 2012 Deans and Santamaria; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.


Modeling the effects of molecular crowding on cerebellar long term depression

Deans Horace

Santamaria Fidel

Directory of Open Access Journals

BMC Neuroscience

Crossref

file:///data/core-remote/dit/data/Springer-OA/pdf/142/aHR0cDovL2xpbmsuc3ByaW5nZXIuY29tLzEwLjExODYvMTQ3MS0yMjAyLTEzLVMxLVA0Ny5wZGY=.pdf

Modeling the effects of molecular crowding on cerebellar long term depression

Abstract

Similar works

Full text

Available Versions

Springer - Publisher Connector

Directory of Open Access Journals

Crossref

Springer - Publisher Connector