Saturation in excitatory synapses of hippocampus investigated by computer simulations

Abstract

The standard view of the synaptic function in excitatory synapses has been deeply questioned by recent experimental data on hippocampal glutamate synapses both for possible receptor nonsaturation and for larger and non-Gaussian peak amplitude fluctuations. Our previous investigations of the mechanisms involved in the variability of the response of hippocampal glutamatergic synapses, carried out by computer simulation of simple Brownian models of glutamate diffusion, furnished initial evidence about their presynaptic character. A new, refined model, reported here, assumes a collision volume for the glutamate molecule and a more realistic description of receptors and their binding dynamics. Based on this model, conditions for AMPA and NMDA receptor saturation have been investigated and new miniature (or quantal) EPSC parameters have been computed. The results corroborate the hypothesis that the lack of AMPA and NMDA receptor saturation and the EPSC stochastic variability are attributable to the small volume of glutamatergic synaptic vesicles and hence to the small number of glutamate molecules diffusing in the cleft after a vesicle release. The investigations better characterize some not well-known elements of the synaptic structure, such as the fusion pore, and provide useful information on AMPA receptor dynamics. Indeed, a nice fit between computed EPSCs and some miniature EPSCs in recent experimental literature allowed for the computation of new transition time values among the different AMPA receptor states through a trial-and-error optimization procedure. Moreover, the model has been used to evaluate two hypotheses on the genesis of the long-term potentiation phenomenon.

The mammalian central nervous synaptic cleft contains a high density of periodically organized complexes

“…This observation definitely makes obsolete the widespread conception of a simple prolongation of the extracellular space. Consequently, neurotransmitters might not be able to diffuse as freely as was previously thought, and computer simulation-based models will have to incorporate these data (35)(36)(37). Similarly, postsynaptic neurotransmitter receptor diffusion, which is implied in synaptic plasticity (38), might be affected by the organized complexes.…”

Random dispersion in excitatory synapse response

“…In fact, the experiments carried out to analyze the binding process imposed the stationarity of the concentration of neurotransmitters within the synaptic cleft and a long period, of the order of milliseconds, of exposition of receptors to Glutamate (Clements et al 1992;Jonas et al 1993). Conversely, in real conditions in which the neurotransmitters are released by a docked vesicle, the flow of neurotransmitters within the cleft is far from stationarity [we can see this also from Figure 6 in Ventriglia and Di Maio (2013b)] and the diffusion process of GLUT within the synaptic cleft is much faster than supposed (100s against 1,000s of microseconds) (see Forti et al 1997;Ventriglia 2004Ventriglia , 2011Ventriglia and Di Maio 2013a). …”

“…The model is simulated on a parallel computer by using an ultra-fast time scale (simulation step = 40 fs). The early results of the simulation demonstrated that intrinsic random variations in basic pre-synaptic elements of the synapse can reproduce some aspects of the observed stochastic variability of the peak amplitude of miniature excitatory post synaptic current (mEPSC) Di Maio 2000, 2003;Ventriglia 2004). Some recent simulations investigated the effects of the inclusion into the model of new data on structural elements such as the presence of filaments extending across the synaptic cleft (Araç et al 2007;Zuber et al 2005; Ventriglia 2011 and references therein), the (increased) size and the (lower) number of post-synaptic receptors and analyzed the consequences of the increase of the number of AMPA receptors-linked to trafficking-on the synaptic response (Ventriglia and Di Maio 2013a).…”

“…Mathematical models-with related computer simulations analyzed almost all the known structural elements of the synapse to stress out how they contribute to shape its response (Agmon and Edelstein 1997;Diamond and Jahr 1997;Freche et al 2011;Kleppe and Robinson 1999;Rabie et al 2006;Savtchenko and Rusakov 2007;Stevens 2003;Trommershäuser et al 2001;Uteshev and Pennefather 1996;Wahl et al 1997). In a series of papers Di Maio 2000, 2003;Ventriglia 2004Ventriglia , 2011Ventriglia and Di Maio 2013a, b), we formulated and investigated a mathematical model of an (hippocampal) excitatory synapse. It is based on the description of the Brownian motion of Glutamate molecules (GLUTs) within the synaptic cleft, by discrete-time Langevin equations, and of their interaction with the structural elements of the synapse, in particular with the post-synaptic receptors.…”

Monte Carlo Simulation of Release of Vesicular Content in Neuroendocrine Cells

“…The plasma membrane and the recording electrode were simulated as two parallel plates. The simulation of the transmitter (free) diffusion in the vesicle (but also in the pore and the space between the plasma membrane and the electrode) followed methods described previously (Glavinović 1999;Ventriglia 2004). Note that the transmitter molecules bound to the gel are not able to diffuse.…”