title: Impact of synaptic localization and subunit composition of ionotropic glutamate receptors on synaptic function: modeling and simulation studies.
abstract: Ionotropic NMDA and AMPA glutamate receptors (iGluRs) play important roles in synaptic function under physiological and pathological conditions. iGluRs sub-synaptic localization and subunit composition are dynamically regulated by activity-dependent insertion and internalization. However, understanding the impact on synaptic transmission of changes in composition and localization of iGluRs is difficult to address experimentally. To address this question, we developed a detailed computational model of glutamatergic synapses, including spine and dendritic compartments, elementary models of subtypes of NMDA and AMPA receptors, glial glutamate transporters, intracellular calcium and a calcium-dependent signaling cascade underlying the development of long-term potentiation (LTP). These synapses were distributed on a neuron model and numerical simulations were performed to assess the impact of changes in composition and localization (synaptic vs extrasynaptic) of iGluRs on synaptic transmission and plasticity following various patterns of presynaptic stimulation. In addition, the effects of various pharmacological compounds targeting NMDARs or AMPARs were determined. Our results showed that changes in NMDAR localization have a greater impact on synaptic plasticity than changes in AMPARs. Moreover, the results suggest that modulators of AMPA and NMDA receptors have differential effects on restoring synaptic plasticity under different experimental situations mimicking various human diseases.
authors.forename: A
authors.initials: A
authors.lastname: Keller
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ambert
authors.forename: Arnaud
authors.initials: A
authors.lastname: Legendre
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bedez
authors.forename: J-M
authors.initials: JM
authors.lastname: Bouteiller
authors.forename: Serge
authors.initials: S
authors.lastname: Bischoff
authors.forename: Michel
authors.initials: M
authors.lastname: Baudry
authors.forename: Saliha
authors.initials: S
authors.lastname: Moussaoui