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The effects of molecular crowding on LTD expression
BMC Neuroscience volume 11, Article number: P6 (2010)
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 . 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  and ran on a large cluster (http://www.cbi.utsa.edu).
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 . Overall, our results show that there is a strong influence of molecular crowding in the activation of biochemical signals in spines.
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.
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
NSF-0923339 and NSF-0934218
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Deans, H., Sherwood, D. & Santamaria, F. The effects of molecular crowding on LTD expression. BMC Neurosci 11, P6 (2010). https://doi.org/10.1186/1471-2202-11-S1-P6
- Purkinje Cell
- AMPA Receptor
- Long Term Depression
- Differential Equation Model
- Cell Synapse