Brownian diffusion of AMPA receptors is sufficient to explain fast onset of LTP.
BACKGROUND
Long-Term Potentiation (LTP) of synapses is thought to be due in part to a change in AMPA Receptor trafficking leading to an increase in the number of AMPA Receptors at the synapse. LTP onset occurs within seconds after the induction signal. A particle-based stochastic simulation software is used to investigate the effect of Brownian diffusion of glutamate receptors on receptor incorporation into the synaptic specialisation and the time-course of LTP expression. The model of the dendritic spine includes receptors diffusing within the membrane, scaffold molecules within the synaptic specialisation capable of binding receptors and a molecular picket-fence surrounding the synaptic membrane area, all features found within the biological system.


RESULTS
During simulations, receptors accumulate rapidly at the post-synaptic density (PSD) from the extra-synaptic membrane under a number of biologically observed conditions. The time of half-saturation, t1/2, defined as the time-point at which half the available scaffold proteins are occupied with receptors, is found to be 710 ms. Different scaffold distributions are shown to have little effect on this time-course. Decreasing the probability of escape of receptors from the PSD domain, thus localising receptors closer to the scaffold proteins, substantially decreases t1/2. A decrease of escape probability from 1 to 0 brings about a non-linear decrease in t1/2 from 710 ms to 390 ms. Release-location of receptors within the spine is found to affect the initial rate of receptor incorporation. We simulate three possible sources of receptors: (i) receptors distributed within the spine extra-synaptic membrane; (ii) receptors from exocytotic vesicles released to the synaptic spine; and (iii) receptors entering the spine from the dendritic shaft through the spine neck. Receptors released from exocytotic vesicles initially accumulate faster than receptors released from the other two sources. A model of glutamate release and glutamate-receptor interaction shows that newly inserted receptors make a substantial contribution to a glutamate evoked response within the observed time-frame.


CONCLUSIONS
Fast accumulation of AMPA Receptors is consistent with experimentally observed fast onset of LTP expression.
Computational Neurobiology Group, EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Dominic P
DP
Tolle
Nicolas
N
Le Novère
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D003198:Computer Simulation; D004058:Diffusion; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology*; D008959:Models, Neurological; D009474:Neurons / Q000737:chemistry* / Q000502:physiology*; D018091:Receptors, AMPA / Q000737:chemistry* / Q000378:metabolism*
D018091:Receptors, AMPA