Variable Binding Probability in AMPA Receptors and AMPARs Trafficking Ventriglia Francesco Istituto di Cibernetica "E.Caianiello" del CNR Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy franco@ulisse.cib.na.cnr.it Di Maio Vito Istituto di Cibernetica "E.Caianiello" del CNR Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy vito.dimaio@cnr.it ABSTRACT Time dependent modifications in AMPA receptors (AMPARs) post-synaptic response in excitatory synapses of brain seem to have a great importance in learning and me mory formation. Although a huge amount of experimental and theoretical researches have been carried on this argument, the basic mechanisms regulating AMPARs activity and AMPARs trafficking remain not completely clarified. In this contest, and to eliminate uncertainties in the synaptic response deriving from the difficulties of the experimental procedures, modeling and simulation studies have been applied to single excitatory synapses [1], [4], [6], [8], [13]. In previous papers we modeled and simulated a hippocampal excitatory synapse at ultra-fast time scale (simulation time step: tens of femtoseconds), to obtain more detailed information on synaptic dynamics [9], [10], [11], [12]. We demonstrated that the stochastic variability of the Excitatory Post Synaptic Current (EPSC) amplitude -reported by experimental studies- can be produced by intrinsic random variations in basic pre-synaptic elements, such as volume and docking position of neurotransmitter vesicles [9], [10], [11]. Moreover, analyzing the effects of structural elements not previously considered by modelers, such as filaments extending across the synaptic cleft at the external of the AZ/PSD volume [2] , [14], it was found that their presence induced a small, but significant, increase in the response of the synapse. For a volume reduction of the free flying space of about 50%, we observed that the increase of the response reached a value of about 20% [12]. In the meantime the experimental research furnished more exact values about the dimensions of post-synaptic receptors -much larger than previously supposed- and about their number -smaller [3], [5]. These new experimental findings were utilized to improve the parameters of the model and to deepen the results of our investigation. The basic geometry of the simulated model of excitatory synapse is constituted by a pre-synaptic active zone (AZ) -where vesicles are docked- juxtaposed to a Post Synaptic Density (PSD) -at a distance of 20 nm- containing AMPA and NMDA receptors [7]. The centers of the two zones usually lie on a common unique axis and different numbers of AMPARs and NMDARs are distributed over the PSD. The two receptor types appear to be mixed together with the AMPARs far exceeding the NMDARs. Both types have been modeled as small cylinders protruding from the PSD zone in the synaptic cleft, each having two binding sites for Glutamate neurotransmitter molecules. Trans-synaptic fibrils, crossing the cleft and disposed according to a regular spacing, have been considered at the external of the AZ/PSD space till to the boundary of the synapse. The mathematical model is based on the description of the Brownian motion of Glutamate molecules within the synaptic cleft through Langevin equations, a well known example of stochastic equations. The Langevin equations, in standard form, appear as: d r i ( t ) = v i ( t ) dt (1)172 BIOCOMP2012 - Abstracts m d v i ( t ) = - g v i ( t ) + 2 e g Ë i ( t ) dt (2) where r i ( t ) and v i ( t ) are, respectively, the position and the velocity of the generic ith Glutamate molecule and m is its molecular mass. Their discrete-time form has been used to simulate the diffusion of neurotransmitter molecules within the synaptic cleft and to obtain their binding times to postsynaptic AMPA and NMDA receptors. The binding times on AMPARs have been used to compute the synaptic response, as EPSC. A new series of simulations has been carried out to take into account the new data. In fact, the availability of more precise information about the structural elements allowed us to investigate in greater detail the dynamics of the binding of glutamate molecules to postsynaptic receptors -by investigating the probability of binding- and the effects of the so-called trafficking of AMPA receptors, which is supposed to be at the base of memory and learning phenomen
Variable binding probability in AMPA receptors and AMPARs trafficking
2012
Abstract
Variable Binding Probability in AMPA Receptors and AMPARs Trafficking Ventriglia Francesco Istituto di Cibernetica "E.Caianiello" del CNR Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy franco@ulisse.cib.na.cnr.it Di Maio Vito Istituto di Cibernetica "E.Caianiello" del CNR Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy vito.dimaio@cnr.it ABSTRACT Time dependent modifications in AMPA receptors (AMPARs) post-synaptic response in excitatory synapses of brain seem to have a great importance in learning and me mory formation. Although a huge amount of experimental and theoretical researches have been carried on this argument, the basic mechanisms regulating AMPARs activity and AMPARs trafficking remain not completely clarified. In this contest, and to eliminate uncertainties in the synaptic response deriving from the difficulties of the experimental procedures, modeling and simulation studies have been applied to single excitatory synapses [1], [4], [6], [8], [13]. In previous papers we modeled and simulated a hippocampal excitatory synapse at ultra-fast time scale (simulation time step: tens of femtoseconds), to obtain more detailed information on synaptic dynamics [9], [10], [11], [12]. We demonstrated that the stochastic variability of the Excitatory Post Synaptic Current (EPSC) amplitude -reported by experimental studies- can be produced by intrinsic random variations in basic pre-synaptic elements, such as volume and docking position of neurotransmitter vesicles [9], [10], [11]. Moreover, analyzing the effects of structural elements not previously considered by modelers, such as filaments extending across the synaptic cleft at the external of the AZ/PSD volume [2] , [14], it was found that their presence induced a small, but significant, increase in the response of the synapse. For a volume reduction of the free flying space of about 50%, we observed that the increase of the response reached a value of about 20% [12]. In the meantime the experimental research furnished more exact values about the dimensions of post-synaptic receptors -much larger than previously supposed- and about their number -smaller [3], [5]. These new experimental findings were utilized to improve the parameters of the model and to deepen the results of our investigation. The basic geometry of the simulated model of excitatory synapse is constituted by a pre-synaptic active zone (AZ) -where vesicles are docked- juxtaposed to a Post Synaptic Density (PSD) -at a distance of 20 nm- containing AMPA and NMDA receptors [7]. The centers of the two zones usually lie on a common unique axis and different numbers of AMPARs and NMDARs are distributed over the PSD. The two receptor types appear to be mixed together with the AMPARs far exceeding the NMDARs. Both types have been modeled as small cylinders protruding from the PSD zone in the synaptic cleft, each having two binding sites for Glutamate neurotransmitter molecules. Trans-synaptic fibrils, crossing the cleft and disposed according to a regular spacing, have been considered at the external of the AZ/PSD space till to the boundary of the synapse. The mathematical model is based on the description of the Brownian motion of Glutamate molecules within the synaptic cleft through Langevin equations, a well known example of stochastic equations. The Langevin equations, in standard form, appear as: d r i ( t ) = v i ( t ) dt (1)172 BIOCOMP2012 - Abstracts m d v i ( t ) = - g v i ( t ) + 2 e g Ë i ( t ) dt (2) where r i ( t ) and v i ( t ) are, respectively, the position and the velocity of the generic ith Glutamate molecule and m is its molecular mass. Their discrete-time form has been used to simulate the diffusion of neurotransmitter molecules within the synaptic cleft and to obtain their binding times to postsynaptic AMPA and NMDA receptors. The binding times on AMPARs have been used to compute the synaptic response, as EPSC. A new series of simulations has been carried out to take into account the new data. In fact, the availability of more precise information about the structural elements allowed us to investigate in greater detail the dynamics of the binding of glutamate molecules to postsynaptic receptors -by investigating the probability of binding- and the effects of the so-called trafficking of AMPA receptors, which is supposed to be at the base of memory and learning phenomenI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
