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The effects of molecular crowding on LTD expression

Long term depression (LTD) in the parallel fiber-Purkinje cell synapse is a well characterized form of synaptic plasticity. The post-synaptic components of LTD are localized in dendritic spines. Spines contain volumes < 1 fL which traditionally have been thought to be well-mixed. Under such assumptions changes in concentration are quickly equilibrated. However, the presence of organelles, spine shape and macro-molecular density could make spines a more tortuous environment for molecules to diffuse and react. We studied the effects of large concentration of non-reacting macro-molecules in the expression of an LTD model.

We translated a recently published well-mixed differential equation model of LTD into a Monte Carlo simulation [1]. We used known diffusion coefficients from the literature or calculated them based on a globular approximation using their molecular weight and the Stokes-Einstein relation. The simulations were implemented in MCell [2] and ran on a large cluster (

The simulation includes all the molecules involved in the phosphorylation of AMPA receptors (AMPAR) after [Ca2+] increase. The simulation includes translocation of molecules to the plasma membrane and diffusion in the cytosol and membrane. The simulation was instantiated in a box of 0.17 µm3, the average volume of a Purkinje cell spine; the post-synaptic density (PSD) occupied one of the box faces. We ran each simulation for 150 seconds, with an increase in [Ca2+] at t = 15 sec. [Ca2+] increases range from 2-10 mM. The stimulus resulted in AMPAR accumulation in the PSD as a function of different levels of [Ca2+]. LTD expression was determined by calculating the percentage drop in AMPAR at t = 150 sec compared from the initial condition. LTD under normal conditions showed a smooth expression of LTD as a function of the stimulus. Molecular crowding in the cytosol was implemented with 120 identical cubes randomly distributed inside the box. The cubes occupied 30 % of the intracellular volume. A classic approach to this problem would suggest that crowding would result in a shift to the right of the LTD curve due to a slowdown in the diffusion of molecules. However, instead, our results show that the sensitivity of LTD to [Ca2+] increases, consistent with non-classical theories of reaction and diffusion due to molecular crowding. LTD under molecular crowding conditions resembles the switch-like response reported in experiments [1]. Overall, our results show that there is a strong influence of molecular crowding in the activation of biochemical signals in spines.


  1. 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. 10.1016/j.neuron.2007.05.014.

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  2. Stiles J, Bartol TM: Monte Carlo methods for simulating realistic synaptic microphysiology using MCell. Computatinal neuroscience. Edited by: De Schutter E. Boca Raton. 2000, CRC

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NSF-0923339 and NSF-0934218

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Correspondence to Fidel Santamaria.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Deans, H., Sherwood, D. & Santamaria, F. The effects of molecular crowding on LTD expression. BMC Neurosci 11 (Suppl 1), P6 (2010).

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  • Purkinje Cell
  • AMPA Receptor
  • Long Term Depression
  • Differential Equation Model
  • Cell Synapse