Abstract
The modeling of glutamate/GABA-glutamine cycling in the brain tissue involving astrocytes, glutamatergic and GABAergic neurons leads to a complex compartmentalized metabolic network that comprises neurotransmitter synthesis, shuttling, and degradation. Without advanced computational tools, it is difficult to quantitatively track possible scenarios and identify viable ones. In this article, we follow a sampling-based computational paradigm to analyze the biochemical network in a multi-compartment system modeling astrocytes, glutamatergic, and GABAergic neurons, and address some questions about the details of transmitter cycling, with particular emphasis on the ammonia shuttling between astrocytes and neurons, and the synthesis of transmitter GABA. More specifically, we consider the joint action of the alanine-lactate shuttle, the branched chain amino acid shuttle, and the glutamine-glutamate cycle, as well as the role of glutamate dehydrogenase (GDH) activity. When imposing a minimal amount of bound constraints on reaction and transport fluxes, a preferred stoichiometric steady state equilibrium requires an unrealistically high reductive GDH activity in neurons, indicating the need for additional bound constants which were included in subsequent computer simulations. The statistical flux balance analysis also suggests a stoichiometrically viable role for leucine transport as an alternative to glutamine for replenishing the glutamate pool in neurons.
Highlights
In the glutamate/GABA-glutamine cycle of neurotransmission, where the ammonium fixation is essential in the synthesis of glutamine in astrocyte, a natural question still waiting for a definitive answer is how the ammonium pool in astrocyte is replenished [1, 2]
In order to shed some light on the nitrogen metabolism and shuttling of amino groups between astrocytes and neurons during inhibition, we propose a complex, eight compartment metabolic model which comprises astrocytes, glutamatergic, and GABAergic neurons, each equipped with separate cytosol and mitochondria
It is commonly accepted that the glutamate and GABA neurotransmitter cycling between neurons and astrocyte is completed by the glutamine transport, following the glutamate/glutamine cycle for excitatory transmission between the glutamatergic neuron and astrocyte, or the GABA/glutamine cycle for the inhibitory transmission between GABAergic neuron and astrocyte
Summary
In the glutamate/GABA-glutamine cycle of neurotransmission, where the ammonium fixation is essential in the synthesis of glutamine in astrocyte, a natural question still waiting for a definitive answer is how the ammonium pool in astrocyte is replenished [1, 2]. The tight coupling between reactions and transports involved in neurotransmitter synthesis and cycling within the complex metabolic network, and the distribution of the functions into different compartments makes it hard, if not impossible, to manually follow the fate of the metabolites and to identify in quantitative terms stoichiometrically feasible steady states. We perform a statistical flux balance analysis of the metabolic pathway during inhibitory activity and verify whether the amino group shuttling mechanisms proposed in the literature are supported by the results of our computational simulations. The focus of the present in silico study is on the synthesis and cycling of the inhibitory neurotransmitter GABA, with the specific aim of elucidating the source and fate of amino groups and ammonia during the GABA cycle. The basic mechanisms of the shuttles are well understood, by considering the joint action of them rather than each one of them separately and isolated from others, a different picture of their role may emerge
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
