Computational investigation of glutamatergic synaptic dynamics: role of ionotropic receptor distribution and astrocytic modulation of neuronal spike timing

Abstract

Glutamatergic synapses and their subsynaptic elements play crucial roles in mediating neuronal communication. Any disruption to the normal functioning of these elements and/or their interactions has implications in neurological disorders. ❧ It is technically difficult to access synaptic space and explore subsynaptic parameters influence on the overall synaptic and higher-order functions through usual experimental methodologies. Computational models complement experimental findings and provide a means for better understanding of such complex systems by providing the framework to look at various dimensions of synaptic functions by simultaneous manipulation of subsynaptic parameters. EONS (Elementary Objects of the Nervous System) is a highly configurable synaptic modeling platform featuring subsynaptic elements and interactions between them. We developed a multi-scale framework, which combines the features of this unified glutamatergic synapse model (EONS) into hippocampal neuron models (within the NEURON simulation environment) within a parallel computing environment. This multi-scale architecture creates a link between molecular level processes and higher order neuronal spiking activity thereby creating a unique powerful tool with direct application to drug design and discovery. ❧ Two main topics were addressed through computer simulations, glutamate diffusion and uptake on synaptic function and neuronal spiking: A) We explored the functional consequences that arise as a result of subsynaptic localization of ionotropic receptors. There is evidence that AMPARs, NMDARs and mGluR exist at different locations within the postsynaptic membrane. These receptors have different kinetics. Given that glutamate released from the pre-synaptic vesicles diffuses across the synaptic cleft, a reasonable hypothesis is that receptors located across the post-synaptic membrane encounter varying levels of glutamate and respond differently. Within this highly configurable synapse model, we varied the location of ionotropic receptors, extracellular environmental factors such as Mg²⁺, astrocytic glutamate uptake. Our simulations using single pulse and paired pulse protocols simulations suggests that it is the interplay between spatial location of AMPAR, density and conductance of these channels and the pre-synaptic pattern of activity combined that influence synaptic potency. B) We explored the influence of astrocytic glutamate uptake on synaptic transmission and neuronal spiking. This was tested with the multi-scale modeling framework developed. Astrocytic glutamate transporter models were added to the synaptic environment to simulate glutamate uptake. The reduced levels of glutamate activated receptors differently and influenced the amplitude and decay time course of EPSCs, which directly had an effect on the neuronal spiking ability. ❧ Overall this model will subsequently help us decipher how targeting molecular elements at the synaptic level can modify network function and could provide a unique method to design therapeutic approaches to alleviate and reverse pathological conditions.