Modeling Glutamatergic Synapses: Insights Into Mechanisms Regulating Synaptic Efficacy

Abstract

The hippocampal formation is critically involved for the long-term storage of various forms of information, and it is widely believed that the phenomenon of long-term potentiation (LTP) of synaptic transmission is a molecular/cellular mechanism participating in memory formation. Although several high level models of hippocampal function have been developed, they do not incorporate detailed molecular information of the type necessary to understand the contribution of individual molecular events to the mechanisms underlying LTP and learning and memory. We are therefore developing new technological tools based on mathematical modeling and computer simulation of the molecular processes taking place in realistic biological networks to reach such an understanding. This article briefly summarizes the approach we are using and illustrates it by presenting data regarding the effects of changing the number of AMPA receptors on various features of glutamatergic transmission, including NMDA receptor-mediated responses and paired-pulse facilitation. We conclude by discussing the significance of these results and providing some ideas for future directions with this approach.

Modeling of the nervous system: From modulation of glutamatergic and gabaergic molecular dynamics to neuron spiking activity

“…These models simulate synaptic function in the presynaptic terminal, in the synaptic cleft (incorporating diffusion processes [6], uptake and astrocytic modulation) and in the postsynaptic spine for both glutamatergic and gabaergic synapses (for more details on the elements contained in the platform, read [7], [8]). All elementary models are written in the Systems Biology Markup Language (SBML) standard.…”

Stability Constraints of Markov State Kinetic Models Based on Routh- Hurwitz Criterion

“…For example by choosing the parameters k 1 =0.7, k 2 =0.2, k 3 =0. 4 and k 4 =0.4 0 =1.0 [28], the constraints necessary to have a stable model are met and a simulation around this operating point is shown in Figure 4. An input 0 =1.0 is applied at 50 msec during 20 msec, and is shown in Figure 4A (black).…”

“…The dotted line on the left corresponds to a GABA concentration equal to -0.0015 mM while the one on the right corresponds to a GABA concentration equal to 6.54 mM. Indeed, for a numerical value of [GABA] less than -0.0015 mM, the constraints d 4 , e 3 and f 2 are negative; whereas for a numerical value of [GABA] greater than 6.54 mM the constraint f 2 is again negative. It is obvious that no negative GABA concentration may be administered.…”

“…Rhenovia Pharma has developed a simulation platform (RHENOMS™) for hippocampal glutamatergic synapses and its integration into complex neuronal networks by combining kinetic receptor models and models of other reactions taking place within synapses [4]. This platform has been used to perform in silico experiments [5] to better understand the dynamics of synaptic transmission under physiological and pathological conditions.…”

Modeling of the nervous system: From molecular dynamics and synaptic modulation to neuron spiking activity

“…These models simulate synaptic function in the presynaptic terminal, in the synaptic cleft (incorporating diffusion processes [5], uptake and astrocytic modulation) and in the postsynaptic spine (for more details on the elements contained in the platform, read [6], [7]). All elementary models are written in the Systems Biology Markup Language (SBML) standard [8].…”