The role of transporters and synaptic cleft morphology in glutamate and GABA homeostasis and their effect on neuronal function

Abstract

The spatiotemporal dynamics of glutamate and gama-aminobutyric acide (GABA) in the synaptic cleft plays a key role in the signal integration in the brain. Since there is no extracellular metabolism of glutamate and GABA, cellular uptake through transporters and diffusion to extracellular space (ECS) regulates the concentration of both neurotransmitters in the cleft. We use the most up to date information about the transporters and synaptic cleft to model the homeostasis of both glutamate and GABA. We show that the models can be used to investigate the role played by different isoforms of transporters, uptake by different neuronal compartments or glia cells, and key parameters determining the morphology of synaptic cleft in the neurotransmitter concentration in the cleft and ECS, and how they shape synaptic responses through postsynaptic receptors. We demonstrate the utility of our models by application to simple neuronal networks and showing that varying the neurotransmitter uptake capacity and synaptic cleft parameters within experimentally observed range can lead to significant changes in neuronal behavior such as the transition of the network between gamma and beta rhythms. The modular form of the models allows easy extension in the future and integration with other computational models of normal and pathological neuronal functions.