A model of cooperative effect of AMPA and NMDA receptors in glutamatergic synapses

Abstract

Glutamatergic synapses play a pivotal role in brain excitation. The synaptic response is mediated by the activity of two receptor types (AMPA and NMDA). In the present paper we propose a model of glutamatergic synaptic activity where the fast current generated by the AMPA conductance produces a local depolarization which activates the voltage- and [Mg(2+)]-dependent NMDA conductance. This cooperative effect is dependent on the biophysical properties of the synaptic spine which can be considered a high input resistance specialized compartment. Herein we present results of simulations where different values of the spine resistance and of the Mg(2+) concentrations determine different levels of cooperativeness between AMPA and NMDA receptors in shaping the post-synaptic response.

Stochastic, structural and functional factors influencing AMPA and NMDA synaptic response variability: a review

“…Other models consider a much complex structure of the synaptic space (see for example [5,16]). Our recent version of the synaptic model has a much more detailed and complex geometry that considers three main compartments for diffusion (vesicle, fusion pore and synaptic cleft), the 3D spaces occupied by receptors in the cleft and also the presence of fibrils [4,9,12,13,17,18,19]. A schematic representation of our synaptic space model is shown in in Figure 2.…”

“…Schikorski and Stevens [22,23] have found values rather different with an average area of 0.4 μm 2 . In our simulation, we have used a mean diameter of the inner cylinder of 220 nm [4,12,13,17,19,24]. The outer cylinder delimits all the synaptic space and corresponds to the maximum width of the spine head.…”

“…For our diffusion process, we use Langevin equations, and, for numerical simulation, we discretize the time with a very small time step [40×10 −15 s (40 femtoseconds)], but not the space. This method, in addition to the fine geometrical representation of the synaptic space, permits a very fine description of the 3D molecular motion [3,4,[10][11][12][13]17,19,24,31,35]. In their standard form, Langevin equations are expressed as…”

“…Our results have shown that, the fast current produced by the AMPA conductance activation, is sufficient to depolarize the membrane unblocking some of the NMDARs at physiological concentrations of Mg 2+ (∼1 mM) [3,4,17]. A matrix U, containing the time of unbinding (t u i, j ∈ U) of the second glutamate molecule, was computed by the B according to a Poisson stochastic process such that…”

“…being t b i, j ∈ B the binding time of the second molecule to the i,j receptor and α r the mean binding duration for the specific receptor type (AMPAR or NMDAR) [4,17]. The parameter α is considerably different between two receptor types because of their different affinities for glutamate, which is higher for NMDARs than for AMPARs.…”